JP2009167219A - Benzimidazole derivative, and use thereof as kdr kinase protein inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide pyrazole-benzimidazole derivatives useful for treating or preventing various diseases including cancer as inhibitors of KDR receptors. <P>SOLUTION: Compounds is represented by formula (IAb) [wherein Ab is a substituted pyrazol-3-yl group, and the other substituents A<SB>1</SB>b, A<SB>2</SB>b, A<SB>3</SB>b, A<SB>4</SB>b, and A<SB>5</SB>b are as defined in the specification]. The compounds of the formula (IAb) may possibly be isomeric forms including racemates, enantioisomers or diastereoisomers and/or may be any possible adducts of the compounds of formula (IAb) with inorganic acids and organic acids or with inorganic bases and organic bases. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a novel benzimidazole derivative, a process for its production, a novel intermediate obtained therefrom, its use as a medicament, a pharmaceutical composition comprising them, and a novel use of such a benzimidazole derivative.

One subject of the present invention is a novel benzimidazole which has an inhibitory action on kinase proteins.
Thus, the benzimidazoles of the present patent application are used in particular for the prevention or treatment of diseases that can be modulated by inhibition of kinase proteins.
Such kinase proteins belong in particular to the following groups: EGFR, Fak, FLK-1, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, flt-1, IGF-1R, KDR, PDGFR, tie2 and VEGFR.
More specifically, the kinase protein is KDR.
Also specifically, the kinase protein is Tie-2.

  Kinase proteins are a family of enzymes that catalyze the phosphorylation of hydroxyl groups of specific protein residues such as tyrosine, serine or threonine residues. Such phosphorylation can greatly alter the function of the protein; thus, kinase proteins play an important role in the regulation of a wide variety of cellular processes, particularly including metabolism, cell proliferation, cell differentiation or cell survival. Among the various cellular functions that involve the activity of kinase proteins, certain processes are attractive targets for treating certain diseases. One example is in particular the regulation of angiogenesis and cell cycle, in which kinase proteins can play a crucial role. These processes are crucial for the growth of solid tumors and also for other diseases.

Angiogenesis is the process by which new blood vessels are formed from existing blood vessels. If the need arises, the vasculature can create a network of new blood vessels to maintain the correct functioning of tissues and organs.
Angiogenesis is a complex multi-step process involving endothelial cell activation, migration, proliferation and survival.
In adults, angiogenesis is almost restricted and appears mainly only in the process of post-injury repair or endometrial angiogenesis (Merenmies et al., Cell Growth & Differentiation, 8, 3-10, 1997). However, uncontrolled angiogenesis is seen in certain medical conditions such as retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration or cancer (solid tumor) (Folkman, Nature Med., 1, 27-31, 1995). Kinase proteins that have been shown to be involved in the angiogenic process are three growth factor receptor tyrosine kinase family members: VEGF-R2 (vascular endothelial growth factor receptor 2 (aka KDR, kinase insertion domain receptor) Or FLK-1)), FGF-R (fibroblast growth factor receptor) and TEK (also known as Tie-2).

In connection with other systems, vascular endothelial growth factor (VEGFR) transmits signals involved in endothelial cell migration, proliferation and survival. The VEGFR family includes VEGFR-1 (Flt-1), VEGFR-2 (KDR) and VEGFR3 (Flt4).
The receptor VEGF-R2, which is expressed only in endothelial cells, binds to the angiogenic growth factor VEGF, thereby acting as a transduction signal medium through activation of its intracellular kinase domain. Thus, direct inhibition of the kinase activity of VEGF-R2 can reduce angiogenesis in the presence of exogenous VEGF (Strawn et al., Cancer Research, 56, 3540-3545, 1996). Has been demonstrated using VEGF-R2 mutants in particular (Millauer et al., Cancer Research, 56, 1615-1620, 1996). The VEGF-R2 receptor is considered to have no function other than the function related to the angiogenic activity of VEGF in adults. Therefore, selective inhibitors of VEGF-R2 kinase activity should show little toxicity.

In addition to this central role in the dynamic angiogenesis process, recent studies suggest that VEGF expression contributes to tumor cell survival after chemotherapy and radiation therapy. Stresses the potential synergistic effect of KDR inhibitors with other drugs (Lee CG, Heijn M. et al. (2000), Cancer Research, 60 (19), 5565-70).
Accordingly, KDR inhibitors are particularly anti-angiogenic agents.
Thus, angiogenesis inhibitors can be used as a first line treatment for the development or regeneration of malignant tumors.
Thus, inhibition or modulation of VEGFR-2 (KDR) provides a powerful novel mechanism of action for the treatment of many solid tumors.

The present patent application thus relates to novel inhibitors of the VEGFR-2 (KDR) receptor, which can be used in particular in oncology, especially for antiangiogenic treatment.
The products of this patent application as KDR inhibitors are in particular the following groups: cancer, in particular breast cancer, colon cancer, lung and prostate cancer, atherosclerosis, degenerative muscle disease, obesity, congestive heart failure, Selected from Parkinson's disease, depression, schizophrenia, stroke, head trauma, spinal cord injury, Alzheimer's disease, neuropathic pain syndrome, amyotrophic lateral sclerosis, cachexia, osteoporosis and visceral fibrotic disease Can be used to treat or prevent certain diseases.

［式中、
ＸはＣ−Ｒ２を示し、そしてＷ、ＹおよびＺは同一であっても、または異っていてもよく、ＣＨまたはＣＲ３を示し；
Ｒ１は、アリールまたはピラゾリル、トリアゾリル、イミダゾリル、インドリル、インダゾリル、チエノピラゾリル、テトラヒドロインダゾリル、テトラヒドロシクロペンタピラゾリル、ジヒドロフロピラゾリル、オキソジヒドロピリダジニル、テトラヒドロピロロピラゾリル、オキソテトラヒドロピロロピラゾリル、テトラヒドロピラノピラゾリル、テトラヒドロピリジノピラゾリル、およびオキソジヒドロピリジノピラゾリル基から選択されるヘテロアリールを示し、これらの全ての基は、場合により、Ｈ、ハロゲン、ハロアルキル、ＯＨ、Ｒ４、ＮＯ２、ＣＮ、Ｓ（Ｏ）ｎＲ４、ＯＲ４、ＮＹ１Ｙ２、ＣＯＲ４、−Ｃ（＝Ｏ）ＮＹ１Ｙ２、−Ｃ（＝Ｏ）ＯＲ４、−Ｃ（＝Ｏ）ＯＨ、−Ｎ（Ｒ６）Ｃ（＝Ｏ）Ｒ４、−Ｎ（Ｒ６）ＳＯ２Ｒ４、−Ｎ（Ｒ６）Ｃ（＝Ｏ）ＮＹ１Ｙ２、−Ｎ（Ｒ６）Ｃ（＝Ｏ）ＯＲ４、−Ｓ（Ｏ）ｎＯＲ４、−Ｓ（Ｏ）ｎＮＹ１Ｙ２、−ＯＣ（＝Ｏ）ＮＹ１Ｙ２、−ＯＳ（Ｏ）ｎＲ４、−ＯＣ（＝Ｏ）Ｒ４、およびチエニル（場合により置換されている）から選択される、１またはそれ以上の基Ｘ１、Ｘ２、またはＸ３で置換されており、 Accordingly, one subject of the present invention is the formula (I):

[Where:
X represents C—R2, and W, Y and Z may be the same or different and represent CH or CR3;
R1 is aryl or pyrazolyl, triazolyl, imidazolyl, indolyl, indazolyl, thienopyrazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, dihydrofuropyrazolyl, oxodihydropyridazinyl, tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl, tetrahydropyrazyl Represents heteroaryl selected from nopyrazolyl, tetrahydropyridinopyrazolyl, and oxodihydropyridinopyrazolyl groups, all of which optionally are H, halogen, haloalkyl, OH, R4, NO2, CN, S ( O) nR4, OR4, NY1Y2, COR4, -C (= O) NY1Y2, -C (= O) OR4, -C (= O) OH, -N (R6) C (= O) R4, -N (R6) ) SO2R , -N (R6) C (= O) NY1Y2, -N (R6) C (= O) OR4, -S (O) nOR4, -S (O) nNY1Y2, -OC (= O) NY1Y2, -OS ( O) substituted with one or more groups X1, X2, or X3 selected from nR4, -OC (= O) R4, and thienyl (optionally substituted);

R2 and R3 are:
R2 and R3 may be the same or different, and H, R4, halogen, haloalkyl, OH, NO2, CN, OR4, COR4, S (O) nR4, -C (= O) NY1Y2 , -C (= O) OR4, -C (= O) OH, -NY1Y2, -N (R6) C (= O) R4, -N (R6) SO2R4, -N (R6) C (= O) NY1Y2 , -N (R6) C (= O) OR4, -S (O) nOR4, -S (O) nNY1Y2, -OC (= O) NY1Y2, and -OC (= O) R4,
Or R2 is H, R4, halogen, haloalkyl, OH, NO2, CN, OR4, COR4, S (O) nR4, -C (= O) NY1Y2, -C (= O) OR4, -C (= O) OH, -NY1Y2, -N (R6) C (= O) R4, -N (R6) SO2R4, -N (R6) C (= O) NY1Y2, -N (R6) C (= O) OR4, -S (O) nOR4, -S (O) nNY1Y2, -OC (= O) NY1Y2, and -OC (= O) R4,
And R3 represents alkyl, haloalkyl, halogen and OR6,
Or a ring based on a 5- to 6-membered carbon containing one or more heteroatoms, wherein R2 and R3 together are the same or different and are selected from O, N and S Form or
Either

R4 represents alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl, and arylalkyl, all these groups optionally being aryl (optionally substituted) Substituted with one or more groups selected from halogen, alkyl, hydroxyalkyl, OH, OR5, C (= O) NY3Y4, NY3Y4, alk-NY3Y4 and C (= O) OR6 ,
R5 represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, and heterocycloalkylalkyl.

Y1 and Y2 are the following: Y1 and Y2 may be the same or different, H, and optionally substituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl Represents arylalkyl, heteroaryl, and heteroarylalkyl,
Or Y1 and Y2 together with the nitrogen atom to which they are attached form a cyclic amino group,
Y3 and Y4 may be the following: Y3 and Y4 may be the same or different and represent hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, or heteroarylalkyl, or , Y3 and Y4, together with the nitrogen atom to which they are attached, form an optionally substituted cyclic amino group,
A5 represents H or alkyl,

R6 is selected from the group corresponding to R5;
All alkyl (or alk, which represents alkyl), alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups in the above groups are halogen atoms and hydroxyl, cyano, alkyl , Alkoxy, acylamino (NH-COalk), -C (= O) OR6, acyl-C (= O) R6, hydroxyalkyl, carboxyalkyl, S (O) n-alk, S (O) n-NH2, S (O) n-NH (alk), S (O) n-N (alk) 2, CF3, OCF3, NO2, arylalkoxy, aryl, heteroaryl, aryloxy, aryloxyalkyl, -C (= O)- One or more groups selected from the group NY3Y4 and NY3Y4, It is further substituted by engagement,
These later-described groups, including alkyl, aryl, and heteroaryl, are themselves optionally halogen atoms, and alkyl groups, carboxyl groups (which are free, salted, or esterified. ), And one or more groups selected from the acylamino group NH—C (O) R 5,
The phenyl group is optionally further substituted with a dioxole group,
n is an integer from 0 to 2]
A compound of

［式中、ＸはＨを示し、Ｒ２またはＲ３は上記で定義されたとおりであり、ここでＷは、必ずＨまたは非置換のアルキルを示す］
該式（Ｉ）の化合物は、可能なすべてのラセミ、鏡像異性またはジアステレオ異性の異性体形態、並びにまた、無機酸および有機酸との付加塩、または無機塩基との付加塩でありうる。 When R1 is an indazolyl group, it is supposed to be a compound of the following formula (I):

[Wherein X represents H and R 2 or R 3 is as defined above, where W always represents H or unsubstituted alkyl]
The compounds of formula (I) can be in all possible racemic, enantiomeric or diastereomeric isomeric forms, and also addition salts with inorganic and organic acids, or addition salts with inorganic bases.

［式中、
ＸａはＣ−Ｒ２ａを示し、そしてＷａ、ＹａおよびＺａは、同一であっても、または異っていてもよく、ＣＨまたはＣＲ３ａを示し；
Ｒ１ａは、アリールまたはピラゾリル、トリアゾリルおよびインダゾリル基から選択されるヘテロアリールを示し、これらの全ての基は、場合により、Ｈ、ハロゲン、ＯＨ、Ｒ４ａ、ＯＲ４ａ、ＮＹ１ａＹ２ａ、Ｓ（Ｏ）ｎＲ４ａ、−Ｃ（＝Ｏ）ＮＹ１ａＹ２ａ、−Ｃ（＝Ｏ）ＯＲ４ａ、−Ｎ（Ｒ６ａ）Ｃ（＝Ｏ）Ｒ４ａ、−Ｎ（Ｒ６ａ）ＳＯ２Ｒ４ａ、−Ｎ（Ｒ６ａ）Ｃ（＝Ｏ）ＮＹ１ａＹ２ａ、−Ｎ（Ｒ６ａ）Ｃ（＝Ｏ）ＯＲ４ａ、−ＯＣ（＝Ｏ）ＮＹ１ａＹ２ａ、−ＯＣ（＝Ｏ）Ｒ４ａ、−ＯＳ（Ｏ）ｎＲ４ａ、およびチエニル（場合によりアルキル基で置換されている）から選択される、１またはそれ以上の基Ｘ１ａ、Ｘ２ａ、またはＸ３ａで置換されており、 Accordingly, one subject of the present invention is the formula (Ia):

[Where:
Xa represents C-R2a and Wa, Ya and Za may be the same or different and represent CH or CR3a;
R1a represents aryl or heteroaryl selected from pyrazolyl, triazolyl and indazolyl groups, all these groups optionally being H, halogen, OH, R4a, OR4a, NY1aY2a, S (O) nR4a, —C (= O) NY1aY2a, -C (= O) OR4a, -N (R6a) C (= O) R4a, -N (R6a) SO2R4a, -N (R6a) C (= O) NY1aY2a, -N (R6a) 1 or selected from C (= O) OR4a, -OC (= O) NY1aY2a, -OC (= O) R4a, -OS (O) nR4a, and thienyl (optionally substituted with an alkyl group) Substituted with further groups X1a, X2a, or X3a;

R2a and R3a are:
R2a and R3a may be the same or different, H, R4a, halogen, OH, OR4a, C (= O) NY1aY2a, -C (= O) OR4a and -C (= O) OH And R3a represents alkyl, halogen and OR6a,
Or R2a represents H, R4a, halogen, OH, OR4a, C (= O) NY1aY2a, -C (= O) OR4a, and -C (= O) OH, and R3a is alkyl, halogen, and Indicate OR6a,
Or R2a and R3a together form an -O-CH2-O- or -O-CH2-CH2-O- ring,
Either
R4a represents alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl, and arylalkyl, all these groups optionally being aryl (optionally substituted) Is substituted with one or more groups selected from halogen, alkyl, hydroxyalkyl, OH, OR5a, C (= O) NY3aY4a, NY3aY4a, alk-NY3aY4a and C (= O) OR6a;

R5a represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocycloalkylalkyl, all of which are optionally substituted;
Y1a and Y2a are the following: Y1a and Y2a may be the same or different, and H, alkyl, alkoxyalkyl, aryloxyalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, cycloalkyl, Aryl and heteroaryl (all these groups are optionally substituted) or a ring in which Y1a and Y2a, together with the nitrogen atom to which they are attached, are optionally substituted Either form a formula amino group,
Y3a and Y4a are as follows: Y3a and Y4a may be the same or different and each represents hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, or heteroarylalkyl, or Either Y3a and Y4a, together with the nitrogen atom to which they are attached, form a cyclic amino group,

A5 represents H or alkyl,
All alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups in the above groups are optionally further substituted with halogen atoms and hydroxyl, cyano, alkyl, alkoxy, acylamino (NH -C (O) R6a), -C (= O) OR6a, acyl-C (= O) R6a, hydroxyalkyl, carboxyalkyl, S (O) n-alk, S (O) n-NH2, S (O ) N-NH (alk), S (O) n-N (alk) 2, CF3, OCF3, NO2, arylalkoxy, aryl, heteroaryl, aryloxy, aryloxyalkyl, -C (= O) -NY3aY4a and Substituted with one or more groups selected from the group NY3aY4a Ri,
These later-described groups, including alkyl, aryl, and heteroaryl, are optionally themselves halogen atoms and alkyl, alkoxy, carboxyl groups (which are free, salified or esterified). And an acylamino group substituted with one or more groups selected from the group NH-C (O) R6a,
The phenyl group is optionally further substituted with a dioxole group,
R6a is selected from the group corresponding to R5a;
n represents an integer of 0 to 2]
A compound of formula (I) as defined above, corresponding to
The compounds of the formula (IA) can be in all possible racemic, enantiomeric or diastereomeric isomeric forms and also addition salts with inorganic and organic acids or addition salts with inorganic bases.

［式中、
ＸはＣ−Ｒ２を示し、そしてＷ、ＹおよびＺは同一であっても、または異っていてもよく、ＣＨまたはＣＲ３を示し；
Ｒ１は、アリールまたは、ピラゾリル、トリアゾリル、イミダゾリル、インドリル、インダゾリル、チエノピラゾリル、テトラヒドロインダゾリル、テトラヒドロシクロペンタピラゾリル、ジヒドロフロピラゾリル、オキソジヒドロピリダジニル、テトラヒドロピロロピラゾリル、オキソテトラヒドロピロロピラゾリル、テトラヒドロピラノピラゾリル、テトラヒドロピリジノピラゾリル、およびオキソジヒドロピリジノピラゾリル基から選択されるヘテロアリールを示し、これらの全ての基は、場合により、Ｈ、ハロゲン、ハロアルキル、ＯＨ、Ｒ４、ＮＯ２、ＣＮ、Ｓ（Ｏ）ｎＲ４、ＯＲ４、ＮＹ１Ｙ２、ＣＯＲ４、−Ｃ（＝Ｏ）ＮＹ１Ｙ２、−Ｃ（＝Ｏ）ＯＲ４、−Ｃ（＝Ｏ）ＯＨ、−Ｎ（Ｒ６）Ｃ（＝Ｏ）Ｒ４、−Ｎ（Ｒ６）ＳＯ２Ｒ４、−Ｎ（Ｒ６）Ｃ（＝Ｏ）ＮＹ１Ｙ２、−Ｎ（Ｒ６）Ｃ（＝Ｏ）ＯＲ４、−Ｓ（Ｏ）ｎＯＲ４、−Ｓ（Ｏ）ｎＮＹ１Ｙ２、−ＯＣ（＝Ｏ）ＮＹ１Ｙ２、−ＯＳ（Ｏ）ｎＲ４、−ＯＣ（＝Ｏ）Ｒ４、およびチエニル（場合により置換されている）から選択される、１またはそれ以上の基Ｘ１、Ｘ２、またはＸ３で置換されており、 Accordingly, one subject of the present invention is the formula (I):

[Where:
X represents C—R2, and W, Y and Z may be the same or different and represent CH or CR3;
R1 is aryl, pyrazolyl, triazolyl, imidazolyl, indolyl, indazolyl, thienopyrazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, dihydrofuropyrazolyl, oxodihydropyridazinyl, tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl, tetrahydro And represents heteroaryl selected from pyranopyrazolyl, tetrahydropyridinopyrazolyl, and oxodihydropyridinopyrazolyl groups, all of which are optionally H, halogen, haloalkyl, OH, R4, NO2, CN, S (O) nR4, OR4, NY1Y2, COR4, -C (= O) NY1Y2, -C (= O) OR4, -C (= O) OH, -N (R6) C (= O) R4, -N ( R6) SO2 4, -N (R6) C (= O) NY1Y2, -N (R6) C (= O) OR4, -S (O) nOR4, -S (O) nNY1Y2, -OC (= O) NY1Y2, -OS Substituted with one or more groups X1, X2, or X3 selected from (O) nR4, -OC (= O) R4, and thienyl (optionally substituted);

R2 and R3 are:
R2 and R3 may be the same or different, H, R4, halogen, haloalkyl, OH, NO2, CN, OR4, COR4, S (O) nR4, -C (= O) NY1Y2, -C (= O) OR4, -C (= O) OH, -NY1Y2, -N (R6) C (= O) R4, -N (R6) SO2R4, -N (R6) C (= O) NY1Y2, -N (R6) C (= O) OR4, -S (O) nOR4, -S (O) nNY1Y2, -OC (= O) NY1Y2, and -OC (= O) R4,
Or R2 is H, R4, halogen, haloalkyl, OH, NO2, CN, OR4, COR4, S (O) nR4, -C (= O) NY1Y2, -C (= O) OR4, -C (= O) OH, NY1Y2, -N (R6) C (= O) R4, -N (R6) SO2R4, -N (R6) C (= O) NY1Y2, -N (R6) C (= O) OR4, -S ( O) nOR4, -S (O) nNY1Y2, -OC (= O) NY1Y2, and -OC (= O) R4,
And R3 represents alkyl, haloalkyl, halogen and OR6,
Or a ring based on a 5- to 6-membered carbon containing one or more heteroatoms, wherein R2 and R3 together are the same or different and are selected from O, N and S Form or
Either
R4 represents alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl, and arylalkyl, all these groups optionally being aryl, OH, OR5, C (═O) substituted with one or more groups selected from NY3Y4, NY3Y4, and C (═O) OR6;
R5 represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, and heterocycloalkylalkyl.

R6 represents H and C1-C4 alkyl;
n represents an integer of 0 to 2,
Y1 and Y2 may be the following: Y1 and Y2 may be the same or different and may be H, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl (all these groups Is optionally substituted with one or more groups selected from hydroxyl, -C (= O) -NY3Y4, -C (= O) OR6, and NY3Y4),
Or Y1 and Y2 together with the nitrogen atom to which they are attached form a cyclic amino group,
Y3 and Y4 may be the following: Y3 and Y4 may be the same or different and represent hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, or heteroarylalkyl, or Y3 and Y4, together with the nitrogen atom to which they are attached, form a cyclic amino group,
A5 represents H or alkyl.
A compound of

［式中、ＸはＨを示し、Ｒ２またはＲ３は上記で定義されたとおりであり、このときＷは必ずＨまたは非置換のアルキルを示す］の式（Ｉ）の化合物が得られるものとされ、
該式（Ｉ）の生成物は、可能なすべてのラセミ、鏡像異性またはジアステレオ異性の異性体形態、並びにまた、無機酸および有機酸との付加塩、または無機塩基との付加塩でありうる。 When R1 represents an indazolyl group, the following:

[Wherein X represents H, R2 or R3 is as defined above, and W must always represent H or unsubstituted alkyl]. ,
The product of formula (I) can be all possible racemic, enantiomeric or diastereomeric isomeric forms, and also addition salts with inorganic and organic acids, or addition salts with inorganic bases .

  Depending on the ring represented by R1 and the number of ring members, it is clear that R1 may comprise 1, 2 or 3 substituents represented by X1, X2 and X3.

In the product of formula (I) and the following description:
The term “alkyl group” refers to linear and optionally branched,
Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl, and also heptyl, octyl, nonyl, and decyl groups, and also linear or branched Meaning their positional isomers in chain form,
The term “hydroxyalkyl group” means an alkyl group as indicated above, which is substituted with at least one hydroxyl group,
The term “alkenyl” means a straight or branched group containing not more than 10 carbon atoms and containing one or more double bonds: in particular vinyl, 1-propenyl. , Allyl, butenyl, and 3-methyl-2-butenyl groups, but also includes, for example, septa-, octa-, non- or deca-dienyl groups, such as octa-2,6-dienyl groups,

The term “alkynyl” includes no more than 10 carbon atoms: in particular straight chain, such as the above alkyl groups containing 2 to 10 carbon atoms and containing one or two triple bonds. Mean a branched or branched group,
The term “alkylthio” specifically includes more than 6 groups such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, hexylthio or isohexylthio groups. Means a linear or branched group containing no carbon atoms, and also a linear or branched regioisomer thereof: of these alkylthio groups, Of these, preferably selected groups are groups containing no more than 4 carbon atoms,
The term “alkoxy group” refers to linear and optionally branched, methoxy, ethoxy, propoxy, isopropoxy, linear, secondary, or tertiary, containing no more than 10 carbon atoms. Means butoxy, pentoxy or hexoxy groups, as well as linear or branched regioisomers thereof,
The term “alkenyloxy group” means straight-chain and branched-O-alkenyl groups having alkenyl as defined above,

The terms “NH (alk)” and “N (alk) (alk)” refer to amino groups that are each substituted with one or two alkyl groups, such alkyl groups being linear or Are branched and selected from the alkyl groups defined above, preferably containing no more than 4 carbon atoms,
The term “acyl” refers to an R—C (O) — group, wherein R is a hydrogen atom, a straight or branched alkyl group containing no more than 6 carbon atoms; Represents an amino, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group as defined above, eg, a group selected from a phenyl or pyrrolidinyl group]; Means for example the formyl group and the acetyl, propionyl, butanoyl, pentanoyl, hexanoyl, benzoyl and pyrrolidinylcarbonyl groups,
The term “acylamino” refers to the groups —C (O) —NH 2, —C (O) —NH (alk), and —C (O) —N (alk) (alk): NH (alk) and N (alk) (alk) have the above-mentioned meanings,
The term “halogen atom” means a chlorine, bromine, iodine or fluorine atom, and preferably a chlorine, bromine or fluorine atom,

The terms “aryl” and “heteroaryl” refer to carbocyclic and heterocyclic, monocyclic or bicyclic saturated groups containing one or more heteroatoms, respectively, which are not more than 12 members. Means
“Saturated or unsaturated, carbocyclic or the same or different containing one or more heteroatoms selected from O, N, NH and S and may contain a —C (O) member The term “heterocyclic, not more than 12-membered monocyclic or bicyclic group” includes the following definitions:
The term “unsaturated carbocyclic group” means in particular a cycloalkyl group,
The term “cycloalkyl group” refers to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups, and more particularly cyclopentyl and cyclohexyl groups;

  The term “monocyclic heterocyclic group” means a saturated or unsaturated, 5- or 6-membered group in which one or more ring members are oxygen, sulfur or nitrogen atoms: Accordingly, such heterocyclic or heterocycloalkyl group means a carbocyclic group into which one or more heteroatoms selected from oxygen, nitrogen and sulfur atoms are inserted, and the heterocyclic group Can contain one or more heteroatoms selected from oxygen, nitrogen and sulfur atoms, and when these heterocyclic groups contain one or more heteroatoms, these heterocyclic It is understood that the heteroatoms of the group can be the same or different. In particular, piperazinyl, piperidyl, morpholinyl, thienyl (eg, substituted with a linear or branched alkyl group of less than 4 carbon atoms, dioxolane, dioxane, dithiolane, thiooxolane, thiooxane, morpholinyl, piperazinyl , 2-thienyl and 3-thienyl), furyl (eg 2-furyl and 3-furyl), pyrimidinyl, pyridyl (eg 2-pyridyl, 3-pyridyl and 4-pyridyl), pyrimidyl, pyrazolinyl, pyrrolyl, thiazolyl, Mention may be made of an isothiazolyl, diazolyl, thiadiazolyl, triazolyl, free or chlorinated tetrazolyl, thiadiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl or 3- or 4-isoxazolyl group. . More particularly, morpholinyl, thienyl (eg, 2-thienyl and 3-thienyl), furyl (eg, 2-furyl), tetrahydrofuryl, thienyl, tetrahydrothienyl, hexahydropyran, pyrrolyl, pyrrolinyl, pyrazolinyl, isoxazolyl, pyridyl , Pyrrolidinyl, imidazolyl, pyrazolyl, pyridazinyl, and oxodihydropyridazinyl groups.

  The term “bicyclic heterocyclic group” refers to a saturated (heteroaryl) or unsaturated 8- to 12-membered group in which one or more ring members are oxygen, sulfur or nitrogen atoms. Means and in particular fused heterocyclic groups contain at least one heteroatom selected from sulfur, nitrogen and oxygen, such as benzothienyl (eg 3-benzothienyl), benzothiazolyl, quinolyl, isoquinolyl, tetralone , Benzofuryl, dihydrobenzofuran, ethylenedioxyphenyl, thiantenyl, benzopyrrolyl, benzimidazolyl, benzoxazolyl, thionaphthyl, indolyl, purinyl, indazolyl, thienopyrazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, dihydrofuropyrazolyl, tetrahydropyrrolo Razoriru, oxo tetrahydropyrrolo pyrazolyl, tetrahydropyrano pyrazolyl, tetrahydropyridinyl Gino pyrazolyl or oxo dihydropyridino - pyrazolyl.

The term “saturated carbocyclic group” (aryl) means in particular phenyl and naphthyl groups, and more particularly phenyl groups. Examples of the carbocyclic group containing a —C (O) member include a tetralone group.
The term “alkylphenyl” refers to a phenyl group substituted with one or more alkyl groups as defined above containing one or more linear or branched, preferably no more than four carbon atoms. means.

The carboxyl group in the compound of formula (I) may be salted or esterified with various groups known to those skilled in the art, for example:
Salt-forming compounds include inorganic bases such as monovalent sodium, potassium, lithium, calcium, magnesium or ammonium, or organic bases such as methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylethanolamine, Tris (hydroxymethyl) aminomethane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine and N-methylglucamine;
Esterified compounds include alkyl groups that form alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, or benzyloxycarbonyl, which alkyl groups include, for example, halogen atoms, hydroxyl, alkoxy, acyl May be substituted with a group selected from an acyloxy, alkylthio, amino or aryl group, for example a chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzyl or phenethyl group.

  Addition salts of inorganic or organic acids with compounds of formula (I) include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, propionic acid, acetic acid, trifluoroacetic acid, formic acid, benzoic acid , Maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxic acid, aspartic acid, ascorbic acid, alkyl monosulfonic acid (eg methanesulfonic acid, ethanesulfonic acid or propanesulfonic acid) , Alkyl disulfonic acids (eg methane disulfonic acid and α, β-ethanedisulfonic acid), aryl monosulfonic acids (eg benzene sulfonic acid), and salts formed with aryl disulfonic acids.

  Stereoisomerism means, for example, monosubstituted cyclohexanes in which the substituent is in the axial or equatorial position, and various possible rotational conformations of ethane derivatives, which have the same structural formula, but the various groups are spatial May be defined in the broad sense of isomerism of compounds arranged differently. However, due to the different spatial arrangement of substituents attached either on the double bond or on the ring, other types of stereoisomerism exist, often referred to as geometric or cis-trans isomerism. The term “stereoisomer” is used in its broadest sense in the present patent application and thus relates to all the compounds indicated above.

［式中、
ＸａはＣ−Ｒ２ａを示し、そしてＷａ、ＹａおよびＺａは同一であっても、または異っていてもよく、ＣＨまたはＣＲ３ａを示し；
Ｒ１ａは、アリールまたは、ピラゾリル、トリアゾリルまたはインダゾリル基から選択されるヘテロアリールを示し、これらの全ての基は、場合により、Ｈ、ハロゲン、ＯＨ、Ｒ４ａ、ＯＲ４ａ、ＮＹ１ａＹ２ａ、Ｓ（Ｏ）ｎＲ４、−Ｃ（＝Ｏ）ＮＹ１ａＹ２ａ、−Ｃ（＝Ｏ）ＯＲ４ａ、−Ｎ（Ｒ６）Ｃ（＝Ｏ）Ｒ４ａ、−Ｎ（Ｒ６）ＳＯ２Ｒ４ａ、−Ｎ（Ｒ６）Ｃ（＝Ｏ）ＮＹ１ａＹ２ａ、−Ｎ（Ｒ６）Ｃ（＝Ｏ）ＯＲ４ａ、−ＯＣ（＝Ｏ）ＮＹ１ａＹ２ａ、および−ＯＣ（＝Ｏ）Ｒ４ａ、−ＯＳ（Ｏ）ｎＲ４、およびチエニル（場合によりアルキル基で置換されている）から選択される、１またはそれ以上の基Ｘ１ａ、Ｘ２ａまたはＸ３ａで置換されており、 Accordingly, one subject of the present invention is the formula (Ia):

[Where:
Xa represents C—R2a and Wa, Ya and Za may be the same or different and represent CH or CR3a;
R1a represents aryl or heteroaryl selected from pyrazolyl, triazolyl or indazolyl groups, all these groups optionally being H, halogen, OH, R4a, OR4a, NY1aY2a, S (O) nR4,- C (= O) NY1aY2a, -C (= O) OR4a, -N (R6) C (= O) R4a, -N (R6) SO2R4a, -N (R6) C (= O) NY1aY2a, -N (R6 ) C (= O) OR4a, -OC (= O) NY1aY2a, and -OC (= O) R4a, -OS (O) nR4, and thienyl (optionally substituted with an alkyl group); Substituted with one or more groups X1a, X2a or X3a,

R2a and R3a are:
R2a and R3a may be the same or different, and H, R4a, halogen, OH, OR4a, C (= O) NY1Y2, -C (= O) OR4a, -C (= O) OH And R3a represents alkyl, halogen and OR6,
Or R2a represents H, R4a, halogen, OH, OR4a, C (═O) NY1Y2, —C (═O) OR4a, —C (═O) OH, and R3a represents alkyl, halogen, and OR6. Or
Or R2a and R3a together form an -O-CH2-O- or -O-CH2-CH2-O- ring,
Either
R4a represents alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heteroarylalkyl or arylalkyl, all these groups optionally being aryl, OH, OR5a, C (= O) NY3aY4a, NY3aY4a And is substituted with one or more groups selected from C (= O) OR6,

R5a represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocycloalkylalkyl;
R6 represents H and C1-C4 alkyl;
n represents an integer of 0 to 2,
Y1a and Y2a may be the following: Y1a and Y2a may be the same or different, and H, alkyl, cycloalkyl, aryl, and heteroaryl (all these groups are optionally hydroxyl,- C (═O) —NY3aY4a, substituted with one or more groups selected from —C (═O) OR6 and NY3aY4a), or Y1a and Y2a are attached Either taken together with the nitrogen atom to form a cyclic amino group,
Y3a and Y4a are as follows: Y3a and Y4a may be the same or different and each represents hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl, or Y3a and Either Y4a, together with the nitrogen atom to which they are attached, forms a cyclic amino group,
A5 represents H or alkyl.
A compound of formula (I) as defined above, corresponding to
The compounds of formula (Ia) can be in all possible racemic, enantiomeric or diastereomeric isomeric forms, and also addition salts with inorganic and organic acids, or addition salts with inorganic bases.

［式中、
Ａは、５−もしくは６−員の単環式基、または１０−員より多くない２環式基のいずれかである飽和複素環式基を示し、これらの環員は、それらの少なくとも２個は窒素原子であり、その他の環員は同一であるかまたは異って、炭素員またはＯ、ＮおよびＳから選択される複素環員であり、この複素環Ａは、場合により、基Ｘ１、Ｘ２またはＸ３について前述される基から選択される、１またはそれ以上の基ＸＡ１、ＸＡ２またはＸＡ３で置換されており、
Ａ１、Ａ２、Ａ３およびＡ４は、同一であっても、または異っていてもよく、水素原子、ハロゲン原子、およびヒドロキシル、アルキル、アルケニル、アルコキシ、ニトロ、シアノ、アリール、ヘテロアリールおよびアリールオキシ基、カルボキシル基（これは、遊離しているか、塩となっているか、アルキル基でエステル化されているか、または基ＮＡ６Ａ７でアミド化されている）から選択され、ここで、Ａ６およびＡ７は同一であってもまたは異っていてもよく、水素原子、および場合により置換されているアルキル、アルコキシアルキル、フェノキシアルキル、アリール、アリールアルキル、シクロアルキル、シクロアルキルアルキル、ヘテロシクロアルキルアルキルおよびヘテロアリールアルキル基から選択されるか、またはＡ６とＡ７はそれらが結合している窒素原子と一緒になって、場合により置換されている５−もしくは６−員の環式基を形成し、 Accordingly, one subject of the present invention is the formula (IA):

[Where:
A represents a saturated heterocyclic group that is either a 5- or 6-membered monocyclic group, or a bicyclic group that is not more than 10-membered, and these ring members include at least two of them. Is a nitrogen atom and the other ring members are the same or different and are carbon members or heterocyclic members selected from O, N and S, this heterocyclic ring A optionally being a group X1, Substituted with one or more groups XA1, XA2 or XA3 selected from the groups described above for X2 or X3;
A1, A2, A3 and A4 may be the same or different, and are a hydrogen atom, a halogen atom, and a hydroxyl, alkyl, alkenyl, alkoxy, nitro, cyano, aryl, heteroaryl and aryloxy group A carboxyl group (which is free, salted, esterified with an alkyl group or amidated with the group NA6A7), wherein A6 and A7 are the same May be different or different, hydrogen atoms and optionally substituted alkyl, alkoxyalkyl, phenoxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl groups Selected from or A6 A7 together with the nitrogen atom to which they are attached, optionally form a cyclic group of 5- or 6-membered substituted,

Two consecutive groups of A1, A2, A3 and A4, together with the benzimidazole group to which they are attached, are identical or differently selected from O, N and S Capable of forming rings based on 5- to 6-membered carbons containing one or more heteroatoms;
A5 represents a hydrogen atom or an alkyl group,
R6b represents hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, phenylalkyl and cycloalkylalkyl;

All alkyl, alkenyl, aryl, heteroaryl, aryloxy, cycloalkyl and heterocycloalkyl groups present in the above groups are optionally halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino. , Phenylamino, phenylalkylamino, acylamino (NH—COR6), —C (═O) OR6b, acyl-C (═O) R6b, hydroxyalkyl, carboxyalkyl, phenoxyalkyl, S (O) n-alk, S (O) n-NH2, S (O) n-NH (alk), S (O) n-N (alk) 2, CF3, OCF3, NO2, CN, phenyl (optionally one or more Substituted with a halogen atom), thienyl, phenoxy, Substituted with one or more groups selected from alkenylalkoxy, —C (═O) —NH 2, —C (═O) —NH (alk), and C (═O) —N (alk) 2 groups And
All the above alkyl, alkenyl, alkoxy and alkylthio groups are straight-chain or branched and contain no more than 4 carbon atoms,
All the phenyl groups of the above groups are optionally further substituted with a dioxole group,
n represents an integer of 0 to 2]
A compound of formula (I) as defined above, corresponding to
The compounds of the formula (IA) are all racemic, enantiomeric or diastereoisomeric forms of the formula and also of the formula (IA) with inorganic and organic acids or with inorganic and organic bases ).

［式中、
Ａａは、ピラゾリル、トリアゾリルまたはインダゾリル基を示し、この複素環Ａａは、場合により、基Ｘ１、Ｘ２またはＸ３について前述される基から選択される、１またはそれ以上の基ＸＡ１、ＸＡ２またはＸＡ３で置換されており、
Ａ１ａ、Ａ２ａ、Ａ３ａおよびＡ４ａは、同一であっても、または異っていてもよく、水素原子、ハロゲン原子、ヒドロキシル、アルキル、アルコキシ、ニトロ、シアノ、フェニルおよびフェノキシ基、およびカルボキシル基（これは、遊離しているか、塩となっているか、アルキル基でエステル化されているか、または基ＮＡ６ａＡ７ａでアミド化されている）から選択され、ここで、Ａ６ａおよびＡ７ａは同一であってもまたは異っていてもよく、水素原子およびアルキル、フェニル、フェニルアルキル、シクロアルキルアルキル、シクロアルキル、フリルアルキル、チエニルアルキルおよびピリジルアルキル基から選択されるか、またはＡ６ａとＡ７ａは、それらが結合している窒素原子と一緒になって、ピロリジニル、ピラゾリジニル、ピラゾリニル、ピペリジル、モルホリノ、または、場合によりその第２の窒素原子上において、アルキルもしくはフェニル基（それら自体場合により置換されている）で置換されているピペラジニル基を形成し、 Accordingly, the subject of the present invention is a compound of formula (IAa):

[Where:
Aa represents a pyrazolyl, triazolyl or indazolyl group, which heterocycle Aa is optionally substituted by one or more groups XA1, XA2 or XA3, selected from the groups mentioned above for the groups X1, X2 or X3 Has been
A1a, A2a, A3a and A4a may be the same or different, and are a hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy, nitro, cyano, phenyl and phenoxy group, and a carboxyl group (this is Wherein A6a and A7a are the same or different from each other, are free, salted, esterified with an alkyl group or amidated with the group NA6aA7a) Optionally selected from a hydrogen atom and an alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, thienylalkyl and pyridylalkyl group, or A6a and A7a are the nitrogen to which they are attached. Together with atoms, pyrrolidinyl, pyrazolidinini , Pyrazolinyl, piperidyl, morpholino, or optionally on its second nitrogen atom form a piperazinyl group substituted with an alkyl or phenyl group (optionally substituted themselves),

Two consecutive groups of A1a, A2a, A3a and A4a contain one or two oxygen atoms optionally substituted together with the benzimidazole group to which they are attached 5 Capable of forming a ring based on a 6-membered carbon;
A5a represents a hydrogen atom or an alkyl group,
The above phenyl and phenoxy groups are optionally halogen atoms and hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, carboxyl (this is Free, salified, or esterified), and substituted with one or more groups selected from dioxol groups,

All the above alkyl, alkoxy and alkylthio groups are linear or branched and contain no more than 6 carbon atoms]
A compound of formula (I) as defined above, corresponding to
The compounds of the formula (IAa) are of the possible racemic, enantiomeric or diastereoisomeric forms and also of the formula (IAa) with inorganic and organic acids or with inorganic and organic bases ).

The substituents X1, X2 and X3 as defined above are in particular one hydrogen atom and the other two may be the same or different, a halogen atom, and OH , R4a, OR4a, CF3, OCF3, NO2, CN, NY1aY2a, acylamino (NH-COR6b), S (O) n-alk, S (O) n-NH2, S (O) n-NH (alk), S (O) n-N (alk) 2, -C (= O) -NH2, -C (= O) -NH (alk), C (= O) -N (alk) 2, -C (= O) OR4a, -N (R6b) C (= O) R4a, -N (R6b) SO2R4a, -N (R6b) C (= O) NY1aY2a, -N (R6b) C (= O) OR4a, -OC (= O ) NY1aY2a and a thienyl group selected from the thienyl group If is substituted with an alkyl group,
R4a, Y1a, Y2a and R6b have the meanings as defined above and alk contains no more than 6 carbon atoms and is optionally substituted as indicated above, linear or A branched alkyl group is shown.

Tables I, II and III below show examples of compounds illustrating the invention, particularly with substituents selected from the groups corresponding to X1, X2 and X3 as defined above.

  All alkylthio groups are optionally oxidized at their sulfur atoms to sulfones or sulfoxides having one or two oxygen atoms.

Thus, the subject of the present invention is that the substituents of the compounds of formula (I) as defined above have any of the meanings described above, and here the aryl groups represent phenyl and naphthyl groups A compound of formula (I);
A heteroaryl group refers to a furyl, thienyl, benzothienyl, thiantenyl, pyridyl, pyrazolyl, benzoimidazolyl, benzofuran, isobenzofuran and dihydrobenzofuran group; a cycloalkyl group refers to a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group; An alkyl group represents a hexahydropyran, piperidyl or morpholino group; a heterocycloalkylalkyl group represents a hexahydropyranalkyl, piperidylalkyl and morpholinoalkyl group; an arylalkyl group includes phenylalkyl, ethylenedioxyphenylalkyl and Represents a naphthylalkyl group; a heteroarylalkyl group represents thienylalkyl, pyridylalkyl, furylalkyl, pyrazolylalkyl; And benzothienylalkyl, dihydrobenzofuranalkyl and benzimidazolealkyl groups; aryloxy groups represent phenoxy and naphthyloxy groups; arylalkoxy groups represent phenylalkoxy and naphthylalkoxy groups; and aryloxyalkyl groups Denotes a phenoxyalkyl group; all these groups are optionally substituted as described in any of the above.

［式中、
Ａは、５−もしくは６−員の単環式基、または１０−員より多くない２環式基のいずれかである飽和複素環式基を示し、これらの環員は、それらの少なくとも２個は窒素原子であり、その他は同一であってもまたは異っていてもよく、炭素員またはＯ、ＮおよびＳから選択される複素環員であり、この複素環Ａは、場合により、ハロゲン原子、アルキル、アルコキシもしくはアルキルチオ基、またはチエニル基（場合によりアルキル基で置換されている）から選択される、１またはそれ以上の基ＸＡ１、ＸＡ２またはＸＡ３で置換されており、 One subject of the present invention is more particularly the formula (IA):

[Where:
A represents a saturated heterocyclic group that is either a 5- or 6-membered monocyclic group, or a bicyclic group that is not more than 10-membered, and these ring members include at least two of them. Are nitrogen atoms, the others may be the same or different and are carbon members or heterocyclic members selected from O, N and S, this heterocyclic ring A optionally being a halogen atom Substituted with one or more groups XA1, XA2 or XA3, selected from: an alkyl, alkoxy or alkylthio group, or a thienyl group (optionally substituted with an alkyl group);

A1, A2, A3 and A4 may be the same or different, and may be a hydrogen atom, a halogen atom, and a hydroxyl, alkyl, alkoxy, nitro, cyano, phenyl and phenoxy group, a carboxyl group (this is Are free, salted, esterified with an alkyl group or amidated with the group NA6A7), wherein A6 and A7 may be the same or different Optionally selected from hydrogen, and alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl and heteroarylalkyl groups, or A6 and A7 together with the nitrogen atom to which they are attached. To form a 5- or 6-membered cyclic group,
Two consecutive groups of A1, A2, A3 and A4, together with the benzimidazole group to which they are attached, are identical or differently selected from O, N and S Capable of forming rings based on 5- to 6-membered carbons containing one or more heteroatoms;

A5 represents a hydrogen atom or an alkyl group,
All the above phenyl, phenoxy, cycloalkyl and heteroarylalkyl groups are optionally halogen atoms and hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino Substituted with one or more groups selected from: phenylalkylamino, carboxyl (which is free, salified or esterified), and a dioxole group;
All the above alkyl, alkoxy and alkylthio groups are linear or branched and contain no more than 6 carbon atoms]
A compound of formula (I) as defined above, corresponding to
The compounds of the formula (IA) are all racemic, enantiomeric or diastereoisomeric forms of the formula and also of the formula (IA) with inorganic and organic acids or with inorganic and organic bases ).

［式中、
Ａｂは、場合により、ハロゲン原子およびＯＨ、アルキル、アルキニル、−ＯＲ６ｂ（アルコキシを含む）、−ＣＯＲ６ｂ、−Ｏ−ＣＯＲ６ｂ、−ＯＳ（Ｏ）ｎＲ６ｂ、−Ｏ（ＣＨ２）ｎ−ＣＯ−Ｒ６ｂ、フェニル、フェニルアルキル、ＣＦ３、ＯＣＦ３、ＮＯ２、ＣＮ、ＮＹ１ｂＹ２ｂ、−ＮＨ−Ｃ（＝Ｏ）ＮＹ１ｂＹ２ｂ、アシルアミノ（ＮＨ−ＣＯ−Ｒ６ｂ）、Ｓ（Ｏ）ｎ−ａｌｋ、Ｓ（Ｏ）ｎ−ＮＹ１ｂＹ２ｂ、−Ｃ（＝Ｏ）−ＮＹ１ｂＹ２ｂ、−Ｃ（＝Ｏ）ＯＲ６ｂ、−ＮＨ−Ｃ（＝Ｏ）Ｒ６ｂ、−ＮＨ−Ｓ（Ｏ）ｎＲ６ｂ、−ＮＨ−Ｃ（＝Ｏ）ＯＲ６ｂ、−Ｎ（Ｒ６ｂ）Ｃ（＝Ｏ）ＮＹ１ｂＹ２ｂ、−ＯＣ（＝Ｏ）ＮＹ１ｂＹ２ｂおよびチエニル基（これらの全ての基は場合により置換されている）から選択される１個または２個の基で置換されているピラゾリルまたはインダゾリル基を示し、
ここで、ＮＹ１ｂＹ２ｂにおいて、Ｙ１ｂおよびＹ２ｂは、同一であってもまたは異っていてもよく、水素、および場合により置換されているアルキル、シクロアルキル、シクロアルキルアルキル、フェニル、ナフチル、フェノキシ、フェニルアルキル、フェニルアルキルチオおよびナフチルアルキルから選択されるか、または、Ｙ１ｂとＹ２ｂは、それらが結合している窒素原子と一緒になって、ピペリジル、ヘキサヒドロフラン、モルホリニルもしくはモルホリニルアルキル基を形成し、 The subject of the invention is also more particularly the formula (IAb):

[Where:
Ab is optionally a halogen atom and OH, alkyl, alkynyl, —OR6b (including alkoxy), —COR6b, —O—COR6b, —OS (O) nR6b, —O (CH2) n—CO—R6b, phenyl , Phenylalkyl, CF3, OCF3, NO2, CN, NY1bY2b, -NH-C (= O) NY1bY2b, acylamino (NH-CO-R6b), S (O) n-alk, S (O) n-NY1bY2b,- C (= O) -NY1bY2b, -C (= O) OR6b, -NH-C (= O) R6b, -NH-S (O) nR6b, -NH-C (= O) OR6b, -N (R6b) 1 or 2 selected from C (= O) NY1bY2b, -OC (= O) NY1bY2b and a thienyl group, all of which are optionally substituted It indicates pyrazolyl or indazolyl group of group substituted,
Here, in NY1bY2b, Y1b and Y2b may be the same or different, and hydrogen and optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy, phenylalkyl , Phenylalkylthio and naphthylalkyl, or Y1b and Y2b together with the nitrogen atom to which they are attached form a piperidyl, hexahydrofuran, morpholinyl or morpholinylalkyl group;

A1b, A2b, A3b and A4b may be the same or different, and are a hydrogen atom, a halogen atom, hydroxyl, alkyl, alkenyl, —OR6b (including alkoxy), —CO—R6b, —O—. COR6b, -OS (O) nR6b, -O (CH2) n-CO-R6b, nitro, cyano, furyl, thienyl, benzothienyl, naphthyl, thianthenyl, phenyl and phenoxy groups, and carboxyl groups (is this free? , Salted, esterified with an alkyl group or amidated with the group NA6bA7b), wherein A6b and A7b may be the same or different, Hydrogen and alkyl, alkoxyalkyl, phenoxyalkyl, phenyl, phenylal , Cycloalkylalkyl, cycloalkyl, furylalkyl, naphthylalkyl, thienylalkyl, piperidylalkyl, pyridylalkyl, benzothienylalkyl, pyrazolylalkyl, dihydrobenzofuranalkyl, hexahydropyranalkyl, ethylenedioxyphenylalkyl and benzimidazolylalkyl groups (All these groups are optionally substituted) or A6b and A7b together with the nitrogen atom to which they are attached form a pyrrolidinyl, morpholino or piperazinyl group. The piperazinyl group is optionally substituted on its second nitrogen atom with an alkyl group (which is itself optionally substituted);
Two consecutive groups of A1b, A2b, A3b and A4b, together with the benzimidazole group to which they are attached, an optionally substituted 4,5-ethylenedioxybenzimidazole group, or Capable of forming an optionally substituted 4,5-methylenedioxybenzimidazole group;
A5b represents a hydrogen atom,

  All the above groups, including alkyl, alkenyl, phenyl, phenoxy, furyl, thienyl, piperidyl, pyridyl, pyrazolyl and benzimidazolyl are optionally substituted with halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino. , Phenylamino, phenylalkylamino, acylamino (NH—COR6b), —C (═O) OR6b, acyl-C (═O) R6b, hydroxyalkyl, carboxyalkyl, phenoxyalkyl, S (O) n-alk, S (O) n-NH2, S (O) n-NH (alk), S (O) n-N (alk) 2, CF3, OCF3, NO2, CN, phenyl (optionally one or more Substituted with halogen atoms), thienyl, pheno One or more groups selected from cis, phenylalkoxy, —C (═O) —NH 2, —C (═O) —NH (alk) and C (═O) —N (alk) 2 groups Has been replaced,

n represents an integer of 0 to 2,
R6b represents hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, pyridyl, thienyl, naphthyl, isoxazole, adamentyl, quinoline, quinolone, dihydroquinolone, -NH-phenyl, phenylalkyl and cycloalkylalkyl, All groups are optionally morpholino, piperidyl, or phenyl (optionally per se halogen atoms, and cyano, CF3, OCF3, alkyl, phenyl-S (O) n-alk-phenyl, alkoxy, NH2, NHalk, N Substituted with one or more groups selected from (alk) 2, SO2NH2, SO2Nalk or SO2N (alk) 2 groups,
All the above alkyl, alkenyl, alkoxy and alkylthio groups are straight-chain or branched and contain no more than 10 carbon atoms,
All the phenyl groups of the above groups are optionally further substituted with a dioxole group], which is a compound of formula (I) as defined above,
The compounds of the formula (IAb) are all of the possible racemic, enantiomeric or diastereoisomeric forms and also of the formula (IAb) with inorganic and organic acids or with inorganic and organic bases ).

Accordingly, one subject of the present invention is in particular the formula (IAb) wherein Ab is optionally a halogen atom and OH, alkyl, alkynyl, alkoxy, phenyl, phenylalkyl, CF3, OCF3, NO2, CN , NY1bY2b, -NH-C (= O) NY1bY2b, acylamino (NH-CO-R6b), S (O) n-alk, S (O) n-NY1bY2b, -C (= O) -NY1bY2b, -C ( = O) OR6b, -NH-C (= O) R6b, -NH-S (O) nR6b, -NH-C (= O) OR6b, -N (R6b) C (= O) NY1bY2b, -OC (= O) represents a pyrazolyl or indazolyl group substituted with one or two groups selected from NY1bY2b and a thienyl (optionally substituted) group;
Here, in NY1bY2b, Y1b and Y2b may be the same or different, and hydrogen and optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy, phenylalkyl, Selected from phenylalkylthio and naphthylalkyl, or Y1b and Y2b together with the nitrogen atom to which they are attached form a piperidyl, hexahydrofuran, morpholinyl or morpholinylalkyl group;

  A1b, A2b, A3b and A4b may be the same or different and are a hydrogen atom, a halogen atom, hydroxyl, alkyl, alkenyl, alkoxy, nitro, cyano, furyl, thienyl, benzothienyl, naphthyl, thiantenyl , Phenyl and phenoxy groups, and carboxyl groups, which are free, salified, esterified with an alkyl group or amidated with the group NA6bA7b, wherein A6b and A7b may be the same or different and are hydrogen and alkyl, alkoxyalkyl, phenoxyalkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, naphthylalkyl, thienylalkyl, piperidyl Selected from alkyl, pyridylalkyl, benzothienylalkyl, pyrazolylalkyl, dihydrobenzofuranalkyl, hexahydropyranalkyl, ethylenedioxyphenylalkyl and benzoimidazolylalkyl groups, all of which are optionally substituted, Or, A6b and A7b, together with the nitrogen atom to which they are attached, form a pyrrolidinyl, morpholino or piperazinyl group, which is optionally on its second nitrogen atom an alkyl group ( Itself is optionally substituted),

Two consecutive groups of A1b, A2b, A3b and A4b, together with the benzimidazole group to which they are attached, an optionally substituted 4,5-ethylenedioxybenzimidazole group, or Capable of forming an optionally substituted 4,5-methylenedioxybenzimidazole group;
A5b represents a hydrogen atom,
All the above groups, including alkyl, alkenyl, phenyl, phenoxy, furyl, thienyl, piperidyl, pyridyl, pyrazolyl and benzimidazolyl are optionally substituted with halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino. , Phenylamino, phenylalkylamino, acylamino (NH—COR6b), —C (═O) OR6b, acyl-C (═O) R6b, hydroxyalkyl, carboxyalkyl, phenoxyalkyl, S (O) n-alk, S (O) n-NH2, S (O) n-NH (alk), S (O) n-N (alk) 2, CF3, OCF3, NO2, CN, phenyl (optionally one or more Substituted with halogen atoms), thienyl, pheno One or more groups selected from di, phenylalkoxy, —C (═O) —NH 2, —C (═O) —NH (alk), and C (═O) —N (alk) 2 groups Is replaced with
n represents an integer of 0 to 2,
R6b represents hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, phenylalkyl and cycloalkylalkyl;

All the above alkyl, alkenyl, alkoxy and alkylthio groups are straight-chain or branched and contain no more than 10 carbon atoms,
All the phenyl groups of the above groups are optionally further substituted with a dioxole group], which is a compound of formula (I) as defined above,
The compounds of the formula (IAb) are all of the possible racemic, enantiomeric or diastereoisomeric forms and also of the formula (IAb) with inorganic and organic acids or with inorganic and organic bases ).

The subject of the present invention is therefore in particular the formula (IAb), wherein Ab represents a pyrazolyl group substituted by one or two groups, one of which is a hydrogen, halogen atom, and Alkyl, alkynyl, -COR6b, phenyl, phenylalkyl, CF3, NO2, CN, NY1bY2b, -NH-C (= O) NY1bY2b, NH-CO-R6b, S (O) n-alk, S (O) n- NY1bY2b, -C (= O) -NY1bY2b, -C (= O) OR6b, -NH-C (= O) R6b, -NH-S (O) nR6b, -NH-C (= O) OR6b, -N (R6b) selected from C (= O) NY1bY2b and a thienyl group (all these groups optionally substituted);
The other group is OH, -OR6b, -O-COR6b, -OS (O) nR6b, -O (CH2) n-CO-R6b and -OC (= O) NY1bY2b groups (all these groups are Is optionally substituted),
Here, in NY1bY2b, Y1b and Y2b may be the same or different, and hydrogen and optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy, phenylalkyl , Phenylalkylthio and naphthylalkyl, or Y1b and Y2b together with the nitrogen atom to which they are attached form a piperidyl, hexahydrofuran, morpholinyl or morpholinylalkyl group;

  A1b, A2b, A3b and A4b may be the same or different, two of them are hydrogen and the other two are the same or different. Hydrogen atom, halogen atom, hydroxyl, alkyl, alkenyl, -OR6b (including alkoxy), -CO-R6b, -O-COR6b, -OS (O) nR6b, -O (CH2) n-CO-R6b , Nitro, cyano, furyl, thienyl, benzothienyl, naphthyl, thiantenyl, phenyl and phenoxy groups, and carboxyl groups (which are free, salted, esterified with alkyl groups, or group NA6bA7b Wherein A6b and A7b may be the same or different , Hydrogen, and alkyl, alkoxyalkyl, phenoxyalkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, naphthylalkyl, thienylalkyl, piperidylalkyl, pyridylalkyl, benzothienylalkyl, pyrazolylalkyl, dihydrobenzofuranalkyl, Selected from hexahydropyranalkyl, ethylenedioxyphenylalkyl and benzimidazolylalkyl groups, all of which are optionally substituted, or A6b and A7b together with the nitrogen atom to which they are attached To form a pyrrolidinyl, morpholino or piperazinyl group, which is optionally on its second nitrogen atom an alkyl group (in itself case). Ri is substituted with has been replaced),

A5b represents a hydrogen atom,
All of the above groups including alkyl, alkenyl, phenyl, phenoxy, furyl, thienyl, piperidyl, pyridyl, pyrazolyl and benzimidazolyl are optionally halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkyl. Amino, phenylamino, phenylalkylamino, acylamino (NH—COR6b), —C (═O) OR6b, acyl-C (═O) R6b, hydroxyalkyl, carboxyalkyl, phenoxyalkyl, S (O) n-alk, S (O) n-NH2, S (O) n-NH (alk), S (O) n-N (alk) 2, CF3, OCF3, NO2, CN, phenyl (optionally one or more in some cases) ), Thienyl, pheno One or more groups selected from cis, phenylalkoxy, —C (═O) —NH 2, —C (═O) —NH (alk) and C (═O) —N (alk) 2 groups Has been replaced,

n represents an integer of 0 to 2,
R6b represents hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, pyridyl, thienyl, naphthyl, isoxazole, adamentyl, quinoline, quinolone, dihydroquinolone, -NH-phenyl, phenylalkyl and cycloalkylalkyl, All groups are optionally morpholino, piperidyl or phenyl (optionally per se halogen atoms and cyano, CF3, OCF3, alkyl, phenyl-S (O) n-alk-phenyl, alkoxy, NH2, NHalk, N (Alk) 2, SO 2 NH 2, SO 2 Nalk or SO 2 N (alk) 2 group)
All the above alkyl, alkenyl, alkoxy and alkylthio groups are linear or molecular and contain no more than 10 carbon atoms,
All the phenyl groups of the above groups are optionally further substituted with a dioxole group], which is a compound of formula (I) as defined above,
The compounds of the formula (IAb) are all of the possible racemic, enantiomeric or diastereoisomeric forms and also of the formula (IAb) with inorganic and organic acids or with inorganic and organic bases ).

The subject of the present invention is therefore in particular the formula (IAb), wherein Ab is optionally substituted with a halogen atom and one or more groups selected from alkyl, alkoxy and thienyl groups, Represents an indazolyl group,
A1b, A2b, A3b and A4b may be the same or different and are a hydrogen atom; a halogen atom; a group of the following types: hydroxyl, alkyl, optionally phenyl (in itself, optionally one Or substituted with alkenyl, alkoxy, nitro, cyano, furyl, optionally substituted with acylCOalk, thienyl, benzothienyl, naphthyl, thiantenyl, optionally substituted Phenyl and phenoxy; and a free, salted, esterified with an alkyl group, or a carboxyl group amidated with the group NA6bA7b, wherein A6b and A7b are the same, Or may be different, hydrogen and a group of the following type: alkyl, Alkoxyalkyl containing no more than carbon atoms, optionally substituted with phenoxyalkyl, phenyl, optionally substituted phenylalkyl, cycloalkylalkyl, cycloalkyl, optionally substituted with acylamino (NH-C (O) alk) Furylalkyl, naphthylalkyl, optionally substituted by alkyl or thienyl, optionally carboxyl group (which is free, salified, or substituted by one or more alkyl groups by Piperidylalkyl, which is esterified with an alkyl group), optionally substituted with one or more groups selected from halogen and CF3, pyridylalkyl, benzothienylalkyl, optionally one or more Pyrazolyl alkyl substituted with an alkyl group, dihydrobenzofuran alkyl, hexa tetrahydropyran alkyl, ethylenedioxy phenylalkyl, and either optionally selected from benzimidazolyl alkyl substituted with 1 or more alkyl groups,

Or, A6b and A7b together with the nitrogen atom to which they are attached form a pyrrolidinyl, morpholino or piperazinyl group, which is optionally substituted with an alkyl group on its second nitrogen atom Has been
Two consecutive groups of A1b, A2b, A3b and A4b, together with the benzimidazole group to which they are attached, an optionally substituted 4,5-ethylenedioxybenzimidazole group, or Capable of forming an optionally substituted 4,5-methylenedioxybenzimidazole group;
R5a represents a hydrogen atom,
The above phenyl, phenoxy and phenylalkyl groups are optionally halogen atoms, hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino and NH-COalk groups, carboxyl groups (this is Free, salted, or esterified with an alkyl group), and hydroxyalkyl, carboxyalkyl, phenoxyalkyl, alkylthio, SO2alk, SO2NH2, SO2-NH (alk), SO2-N (alk ) 2, CF 3, OCF 3, NO 2, CN, phenyl (which is itself optionally substituted with one or more halogen atoms), thienyl, phenoxy, phenylalkoxy, —C (═O) —NH 2, —C ( O) -NH (alk), C (= O) -N (alk) is selected from 2 and C (O) CH3 group is substituted with one or more groups,
All the above alkyl or alk, alkenyl, alkoxy and alkylthio groups are linear or molecular chain and contain no more than 4 carbon atoms,
All the phenyl groups of the above groups are optionally further substituted with a dioxole group], which is a compound of formula (I) as defined above,
The compounds of the formula (IAb) are all of the possible racemic, enantiomeric or diastereoisomeric forms and also of the formula (IAb) with inorganic and organic acids or with inorganic and organic bases ).

Thus, the subject of the present invention is especially of the formula (IAb) wherein Ab, A1b, A2b, A3b, A4b and A5b have any of the meanings described above,
And when one of A1b, A2b, A3b and A4b represents a carboxyl group amidated with the group NA6bA7b, one of A6b and A7b is a hydrogen atom or an alkyl group and the other of A6b and A7b Are selected from the groups defined for A6b and A7b, or A6b and A7b together with the nitrogen atom to which they are attached form a 5- or 6-membered cyclic group;
Other substituents of the compound of formula (I) have any of the meanings described above]
A compound of formula (I) as defined above, equivalent to
The compounds of the formula (IAb) are all of the possible racemic, enantiomeric or diastereoisomeric forms and also of the formula (IAb) with inorganic and organic acids or with inorganic and organic bases ) Product addition salts.

Thus, the subject of the present invention is in particular the formula (I) as defined above, wherein X, W, Y and Z are two or three of which represent CH and the others are CR2 or CR3 Selected from the group corresponding to
R2, R3 and the other substituents of the compound of formula (I) have any of the meanings defined above]
The compounds of the formula (I) are of all possible racemic, enantiomeric or diastereoisomeric forms, and also of the formula (I) with inorganic and organic acids or with inorganic and organic bases ) Product addition salts.

Accordingly, the present invention particularly relates to the formula (IA) defined above, wherein A1, A2, A3 and A4 are those wherein two or three of them represent hydrogen atoms and the others are A1, A2, Selected from the groups corresponding to A3 and A4, and if appropriate may form a dioxole group,
Other substituents of the compound of formula (IA) have any of the meanings defined above]
The compounds of the formula (IA) are all racemic, enantiomeric or diastereoisomeric forms of the formula and also of the formula (IA) with inorganic and organic acids or with inorganic and organic bases ).

［式中、
Ａａは、ピラゾリル、トリアゾリルまたはインダゾリル基を示し、この複素環Ａａは、場合により、ハロゲン原子、アルキル、アルコキシまたはアルキルチオ基、および場合によりアルキル基で置換されているチエニル基から選択される、１またはそれ以上の基ＸＡ１、ＸＡ２またはＸＡ３で置換されており、 The subject of the invention is also more particularly the formula (IAa):

[Where:
Aa represents a pyrazolyl, triazolyl or indazolyl group, the heterocyclic ring Aa optionally selected from a halogen atom, an alkyl, alkoxy or alkylthio group, and a thienyl group optionally substituted with an alkyl group, 1 or Substituted with further groups XA1, XA2 or XA3;

A1a, A2a, A3a and A4a may be the same or different and are a hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy, nitro, cyano, phenyl and phenoxy group, and a carboxyl group (this is Free, salted, esterified with an alkyl group or amidated with the group NA6aA7a), wherein A6a and A7a may be the same or different Selected from a hydrogen atom and an alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, thienylalkyl and pyridylalkyl group, or A6a and A7a are Together with the nitrogen atom, pyrrolidinyl, pyrazoli Cycloalkenyl, pyrazolinyl, piperidyl, morpholino or when the on its second nitrogen atom, form a piperazinyl group substituted with an alkyl or phenyl group (optionally substituted themselves),
Two consecutive groups of A1a, A2a, A3a and A4a contain one or two oxygen atoms optionally substituted together with the benzimidazole group to which they are attached 5 Capable of forming a ring based on a 6-membered carbon;
A5a represents a hydrogen atom or an alkyl group,
The above phenyl and phenoxy groups are optionally halogen atoms and hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, carboxyl (this is Free, salted or esterified), and substituted with one or more groups selected from dioxol groups,
All the above alkyl, alkoxy and alkylthio groups are linear or molecular and contain no more than 6 carbon atoms]
A compound of formula (I) as defined above, corresponding to
The compounds of the formula (IAa) are of the possible racemic, enantiomeric or diastereoisomeric forms and also of the formula (IAa) with inorganic and organic acids or with inorganic and organic bases ).

  One subject of the present invention more particularly is the formula (I) as defined above, wherein R represents a pyrazolyl or indazolyl group and the other substituents have the meanings indicated above or below. ].

Preferred compounds specifically mentioned are those of formula (IAa) [wherein
Aa represents a pyrazolyl or indazolyl group optionally substituted as indicated above and below;
A1a, A2a, A3a and A4a are:
-A1a represents hydrogen or carboxyl or together with the adjacent ring member A2a forms a ring;
A4a represents hydrogen or carboxyl, or together with the adjacent ring member A3a forms a ring,
-A2a represents a free, salified, esterified carboxyl group with an alkyl group (optionally substituted), or an amidated carboxyl as indicated above or below,
-A2a and A3a represent two optionally substituted alkyl groups,
Selected from the meaning of
-A5a represents hydrogen].

［式中、
Ａｂは、場合により、ハロゲン原子、およびアルキル、アルコキシおよびチエニル基から選択される１またはそれ以上の基で置換されている、ピラゾリルまたはインダゾリル基を示し、
Ａ１ｂ、Ａ２ｂ、Ａ３ｂおよびＡ４ｂは、同一であっても、または異っていてもよく、水素原子、ハロゲン原子、ヒドロキシル、アルキルおよびアルコキシ、ニトロ、シアノ、フェニルおよびフェノキシ基、およびカルボキシル基（これは遊離しているか、塩となっているか、アルキル基でエステル化されているか、または基ＮＡ６ｂＡ７ｂでアミド化されている）から選択され、ここで、Ａ６ｂおよびＡ７ｂは、同一であってもまたは異っていてもよく、アルキル、フェニル、フェニルアルキル、シクロアルキルアルキル、シクロアルキルおよびフリルアルキル基から選択されるか、またはＡ６ｂとＡ７ｂは、それらが結合している窒素原子と一緒になって、ピロリジニル、モルホリノ、もしくは場合によりその第２の窒素原子上において、アルキル基で置換されているピペラジニル基を形成し、 One subject of the present invention is even more particularly of formula (IAb):

[Where:
Ab represents a pyrazolyl or indazolyl group optionally substituted with a halogen atom and one or more groups selected from alkyl, alkoxy and thienyl groups;
A1b, A2b, A3b and A4b may be the same or different, and are a hydrogen atom, halogen atom, hydroxyl, alkyl and alkoxy, nitro, cyano, phenyl and phenoxy group, and a carboxyl group (this is Free, salted, esterified with an alkyl group or amidated with the group NA6bA7b), wherein A6b and A7b may be the same or different Optionally selected from alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl and furylalkyl groups, or A6b and A7b together with the nitrogen atom to which they are attached, pyrrolidinyl, On the morpholino, or optionally on its second nitrogen atom Forming a piperazinyl group substituted with an alkyl group,

Two consecutive groups of A1b, A2b, A3b and A4b together with the benzimidazole group to which they are attached are optionally substituted 4,5-ethylenedioxybenzimidazole groups or 4 , 5-methylenedioxybenzimidazole group can be formed,
A5b represents a hydrogen atom,
The above phenyl and phenoxy groups are optionally halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, and carboxyl groups (which are free or chlorinated). Or is esterified) and is substituted with one or more groups selected from
All the above alkyl, alkoxy and alkylthio groups are linear or molecular and contain no more than 4 carbon atoms]
A compound of formula (I) as defined above, corresponding to
The compounds of the formula (IAb) are all of the possible racemic, enantiomeric or diastereoisomeric forms and also of the formula (IAb) with inorganic and organic acids or with inorganic and organic bases ).

One subject of the present invention is the product of formula (I) as defined above, more particularly corresponding to the following formula:
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-methylamide 2- ( 1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-ethylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-isopropylamide 2- (1H -Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenethylamide 2- (1H -Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-morpho Noamido 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (N′-methylpiperazino) amide 2- (1H-indazol-3-yl) -1H-benzimidazole-5 Carboxylic acid N-pyrrolidinoamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (isobutyl) amide 2- (1H-indazol-3-yl) -1H-benzimidazole -5-carboxylic acid N- (cyclohexylmethyl) amide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (2-furfuryl) amide 2- (1H-indazole-3- Yl) -1H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide

Methyl 2- (1H-indazol-3-yl) -3H-benzimidazole 5-carboxylate 5,6-dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole 5-methoxy-2- ( 1H-indazol-3-yl) -1H-benzimidazole 2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 5-bromo 2- (1H-indazol-3-yl) -3H -Benzimidazole 2- (5-Ethoxy-2H-pyrazol-3-yl) -1H-benzimidazole-4-carboxylic acid

5,6-Dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -1H-benzimidazole 5,6-Dimethyl-2- (5-thiophen-2-yl-2H-pyrazol-3-yl) ) -1H-benzimidazole 2- (4-bromo-2H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole 2- (5-ethyl-2H-pyrazol-3-yl) -5, 6-dimethyl-1H-benzimidazole 2- (5-ethyl-2H-pyrazol-3-yl) -4,5-ethylenedioxy-1H-benzimidazole 2- (5-ethyl-2H-pyrazol-3-yl) ) -5-Methoxy-1H-benzimidazole 2- (5-ethyl-2H-pyrazol-3-yl) -4-hydroxy-1H-benzimidazole 2- (5-ethyl-2H) Pyrazol-3-yl) -5-bromo -1H- benzimidazole

2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4- (aminosulfonyl) benzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-Bromobenzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4- (methanesulfonyl) benzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole -5-carboxylic acid 4-nitrobenzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-methylbenzylamide 2- (1H-indazol-3-yl) -1H- Benzimidazole-5-carboxylic acid (6-chloropyridin-3-ylmethyl) amide 2 (1H-Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (2,3-dihydrobenzofuran-5-ylmethyl) amide 2- (1H-indazol-3-yl) -1H-benzimidazole-5 -Carboxylic acid 2- (methylsulfanyl) benzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (benzo [b] thiophen-3-ylmethyl) amide 2- (1H-indazole) -3-yl) -1H-benzimidazole-5-carboxylic acid 3-methylbenzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-chlorobenzylamide 2- (1H -Indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 2- (me Rusurufaniru) benzylamide.

One subject of the present invention is a compound of formula (I) as defined above, more particularly corresponding to the following formula:
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-methylamide 2- ( 1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-ethylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-isopropylamide 2- (1H -Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenethylamide 2- (1H -Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-morpho Noamido

2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (N′-methyl-piperazino) amide 2- (1H-indazol-3-yl) -1H-benzimidazole-5 -Carboxylic acid N-pyrrolidinoamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (isobutyl) amide 2- (1H-indazol-3-yl) -1H-benzo Imidazole-5-carboxylic acid N- (cyclohexylmethyl) amide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (2-furfuryl) amide 2- (1H-indazole-3) -Yl) -1H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide 5-methoxy-2- (1 H-indazol-3-yl) -1H-benzimidazole 2- (5-ethyl-2H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole 2- (5-ethyl-2H-pyrazole- 3-yl) -4,5-ethylenedioxy-1H-benzimidazole 2- (5-ethyl-2H-pyrazol-3-yl) -5-methoxy-1H-benzimidazole 2- (5-ethyl-2H- Pyrazol-3-yl) -4-hydroxy-1H-benzimidazole 2- (5-ethyl-2H-pyrazol-3-yl) -5-bromo-1H-benzimidazole.

One subject of the present invention is the product of formula (I) as defined above, more particularly corresponding to the following formula:
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4- (aminosulfonyl) benzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-Bromobenzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4- (methanesulfonyl) benzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole -5-carboxylic acid 4-nitrobenzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-methylbenzylamide 2- (1H-indazol-3-yl) -1H- Benzimidazole-5-carboxylic acid (6-chloropyridin-3-ylmethyl) amide 2 (1H-Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (2,3-dihydrobenzofuran-5-ylmethyl) amide 2- (1H-indazol-3-yl) -1H-benzimidazole-5 -Carboxylic acid 2- (methylsulfanyl) benzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (benzo [b] thiophen-3-ylmethyl) amide 2- (1H-indazole) -3-yl) -1H-benzimidazole-5-carboxylic acid 3-methylbenzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-chlorobenzylamide 2- (1H -Indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 2- (me Rusurufaniru) benzylamide.

The subject of the invention is also a process for the preparation of a compound of formula (I) as defined above, wherein formula (D):
R1′-COOH (D)
Wherein R1 ′ has the meaning described above for R1, wherein a possible reactive functional group is optionally protected with a protecting group, and is subjected to an esterification reaction, Formula (II):
R1'-COOalk (II)
[Wherein R1 ′ has the above-mentioned meaning and alk represents an alkyl group] is converted into an acid ester, which is subjected to a reduction reaction to give a formula (III):
R1′-CH2OH (III)
[Wherein R1 ′ has the above-mentioned meaning] and is oxidized to give the formula (IV):
R1'-CHO (IV)
Wherein R1 ′ has the meaning described above,

［式中、Ｗ’、Ｘ’、Ｙ’およびＺ’は、それぞれＷ、Ｘ、ＹおよびＺについて上述した意味を有し、ここで、ありうる反応性の官能基は場合により保護基で保護されている］のジアミンと反応させて、式（Ｉ’）：

［式中、Ａ５’は、Ａ５について上記に記載された意味を有し、ここで、ありうる反応性の官能基は場合により保護基で保護されており、そしてＲ１’、Ｗ’、Ｘ’、Ｙ’およびＺ’は上述の意味を有する］の化合物を得ることを特徴とし、 A compound of formula (D) or a compound of formula (IV) as defined above is then converted to formula (V):

[Wherein W ′, X ′, Y ′ and Z ′ have the meanings given above for W, X, Y and Z, respectively, where possible reactive functional groups are optionally protected with protecting groups. In the formula (I ′):

Wherein A5 ′ has the meaning described above for A5, where possible reactive functional groups are optionally protected with protecting groups and R1 ′, W ′, X ′. , Y ′ and Z ′ have the meanings described above]

The compound of formula (I ′) may be the product of formula (I) and this compound may be optionally and optionally obtained to obtain a compound of formula (I) or other compounds. Can be subjected to one or more of the following conversion reactions in any order:
a) esterification reaction of acid functional group,
b) Saponification reaction of ester functional group to acid functional group,
c) oxidation reaction of alkylthio group to the corresponding sulfoxide or sulfone,
d) Conversion reaction of ketone functional group to oxime functional group,
e) reduction reaction of a free or esterified carboxyl function to an alcohol function,
f) Conversion reaction of alkoxy functional group to hydroxyl functional group, or conversion reaction of hydroxyl functional group to alkoxy functional group,
g) oxidation reaction of alcohol functionality to aldehyde, acid or ketone functionality,
h) conversion reaction of nitrile group to tetrazolyl,
i) Removal reaction of the protecting group supported on the protected reactive functional group,
j) a salt-forming reaction with an inorganic or organic acid or with a base to obtain the corresponding salt;
k) resolution of the racemic form into resolution products,
In this way, the compounds of formula (I) are obtained in any possible racemic, enantiomeric or diastereoisomeric form.

［式中、Ａ１’、Ａ２’、Ａ３’およびＡ４’は、それぞれＡ１、Ａ２、Ａ３およびＡ４について上述した意味を有し、ここで反応し得る官能基は場合により保護基で保護されている］のジアミンと反応させて、式（ＩＡ’）：

［式中、Ａ５’はＡ５について上記に記載された意味を有し、ここで、反応し得る官能基は場合により保護基で保護されており、そしてＡ１’、Ａ２’、Ａ３’およびＡ４’は上述の意味を有する］の化合物とすることを特徴とし、
該式（ＩＡ’）の化合物は、式（ＩＡ）の化合物であってよく、そしてこの生成物を、式（ＩＡ）の化合物またはその他の化合物を得るために、所望により、および必要に応じて、任意の順番で、上記で定義された１またはそれ以上の変換反応ａ）〜ｋ）に付すことができ、
このようにして、得られる該式（ＩＡ）の化合物は、任意の可能なラセミ、鏡像異性またはジアステレオ異性の異性体形態である。 The subject of the present invention is more particularly a process for the preparation of a compound of formula (I) as defined above, corresponding to formula (IA), wherein formula (D):
A'-COOH (D)
Wherein A ′ has the meaning described above for A, wherein the functional group capable of reaction is optionally protected with a protecting group, an acid of the formula (II) is subjected to an esterification reaction. :
A'-COOalk (II)
[Wherein A ′ has the above-mentioned meaning and alk represents an alkyl group], which is an acid ester, which is subjected to a reduction reaction to obtain a compound represented by the formula (III):
A'-CH2OH (III)
[Wherein A ′ has the above-mentioned meaning] and this is oxidized to form the formula (IV):
A'-CHO (IV)
Wherein the product of formula (D) or product of formula (IV) as defined above is represented by formula (V):

[Wherein A1 ′, A2 ′, A3 ′ and A4 ′ have the meanings given above for A1, A2, A3 and A4, respectively, wherein the functional groups which can react here are optionally protected with protecting groups. And a diamine of formula (IA ′):

[Wherein A5 ′ has the meaning described above for A5, wherein the reactive functional group is optionally protected with a protecting group, and A1 ′, A2 ′, A3 ′ and A4 ′ Has the above-mentioned meaning].
The compound of formula (IA ′) may be a compound of formula (IA) and the product is optionally and optionally obtained to obtain a compound of formula (IA) or other compounds Can be subjected in any order to one or more conversion reactions a) to k) as defined above;
In this way, the resulting compound of formula (IA) is in any possible racemic, enantiomeric or diastereomeric isomeric form.

  In addition, such a reaction for converting a substituent to another substituent should be performed on the starting material and also on the above-mentioned intermediate before the continuous synthesis reaction according to the reaction shown in the above step. Can do.

  Under the preferred conditions for carrying out the invention, the above steps can be carried out as shown in the following scheme: The reaction is carried out according to the usual conditions known to the person skilled in the art, for example according to the reaction conditions shown below: It can be carried out.

Of the products of formula (I) of this patent application, certain products in which R1 represents a pyrazolyl or indazolyl group can be obtained from an acid precursor according to the following scheme:

The following scheme shows a preferred synthetic route for the product of formula (I) of this patent application:
I) Benzimidazole-indazole systems, ie products of formula (I) in which R1 represents indazolyl:
Stage 1: Formation of aldehyde of formula (IV) :

Ａ２もしくはＡ３、またはＡ１もしくはＡ４がカルボキシル基を示す場合、Ａ２もしくはＡ３、またはＡ１もしくはＡ４はそれぞれ、当業者に公知の標準方法により、特に下記のペプチドカップリングの標準方法に従い、アミドに変換することができる。 Second stage: Formation of the product of formula (I) :

When A2 or A3, or A1 or A4 represents a carboxyl group, A2 or A3, or A1 or A4, respectively, is converted to an amide by standard methods known to those skilled in the art, in particular according to the standard methods for peptide coupling described below. be able to.

In these compounds, the substituents A1, A2, A3, A4, A6, A7, X1, X2 and X3 have the above-mentioned meanings.
I) Benzimidazole-pyrazole series, ie compounds of formula (I) in which R1 represents pyrazolyl:

More generally, there are the following synthetic schemes:

In the resulting compound of formula (IA), X1 may in particular be H and X2 may be optionally substituted thienyl.
In these compounds, for example, A1 and A4 may be H and A3 and A4 may be alkyl.
In the above products, the substituents A1, A2, A3, A4, A5, A6, A5, X1 and X2 have the above-mentioned meanings.

を、

で置き換えることにより同様に該工程を実施することができ、このようにして相当する化合物が得られる。 In the above scheme,

The

Can be carried out in the same way by substituting with and thus the corresponding compound is obtained.

As a non-limiting example illustrating the implementation of the process of this patent application, the synthesis of the four compounds of formula (I) of this patent application can be illustrated by the following scheme:
Also, the following synthetic route can be used for the production of the product of this patent application.

Conversion of Form A intermediate to Form B product by methods known to those skilled in the art

  The substituents R′1 to R′4 and R ′ do not necessarily represent only protecting groups, but can also represent functional groups that allow introduction of new substituents.

The acid ester constituted by the product of formula (II) can be obtained, if necessary, from the corresponding acid according to the usual methods and in particular according to the methods described above.
Such acids are commercially available, for example 3-carboxyindazole.
In the compounds of the formula (II), the group A ′ is in particular a pyrazolyl or indazolyl group.

The oxidation reaction of the alcohol of formula (III) to the corresponding aldehyde of formula (IV) can be carried out by conventional techniques, for example using manganese peroxide or Swern type chromium PCC salts.
The aldehyde of formula (IV) thus obtained is reacted with a diamine of formula (V) in the presence of NaHSO ₄ , particularly in a solvent such as refluxing DMF.
Among the diamines of formula (V), mention may be made, for example, of ortho-dianilines optionally substituted with one or more substituents selected from the groups corresponding to A1, A2, A3 and A4.

Optionally, as shown in the above scheme, pyrazolyl groups can be formed by reacting, in particular, alkyl acetylenedicarboxylates, such as methyl acetylenedicarboxylate, with hydrazine.
Some of the starting materials of formulas (II) and (V) are known, can be obtained commercially or can be prepared according to conventional methods known to those skilled in the art.
Certain starting materials may also be prepared, in particular, from commercially available compounds, for example by subjecting them to one or more of the reactions described above in a) to k) and under the reaction conditions described above. Can do.

The experimental part below shows examples of such starting materials.
The following references which can be used for the preparation of benzimidazole, pyrazole or indazole in the context of the present invention are also mentioned:
-GR Newkome, WW Paudler, Contemporary Heterocyclic Chemistry, Syntheses, Reactions and Applications, J. Wiley, 1982
-Preston, Heterocyclic Compounds, Benzimidazoles and congeneric tricyclic compounds, J. Wiley, 1981
-Behr, Fusco, Jarboe, Heterocyclic Compounds, Pyrazoles, Pyrazolines, Pyrazolidines, indazoles and condensed rings, J. Wiley, 1967.

According to the groups corresponding to R1 ′, W ′, X ′, Y ′, A ′, A1 ′, A2 ′, A3 ′, A4 ′ and A5 ′, the compound of formula (I ′) or (IA ′) has the formula A compound of (I) or (IA) may or may not be configured, and a compound of formula (I) or (IA) may be provided, or one of a) to k) above Alternatively, these can be converted to other compounds of formula (I) or (IA) by subjecting them to further reactions.
Thus, in the above reactions, various reactive functional groups that may be generated by some compounds may be protected as required: these include, for example, hydroxyl, acyl, free carboxyl or amino, and monoalkylamino And can be protected with a suitable protecting group.

The following non-comprehensive list of examples of reactive functional group protection can be given:
The hydroxyl group can be protected with an alkyl group such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl or acetyl,
The amino group can be protected with, for example, acetyl, trityl, benzyl, tert-butoxycarbonyl, BOC, benzyloxycarbonyl or phthalimide groups, or other groups known in peptide chemistry,
-Protecting acyl groups such as formyl groups in the form of cyclic or acyclic ketals or thioketals, such as dimethyl or diethyl ketals, or ethylene dioxy ketals, or diethyl thio ketals or ethylene dithio ketals; Can
The acidic functional groups in the above products are optionally primary or secondary at room temperature, for example in methylene chloride, for example in the presence of 1-ethyl-3- (dimethylaminopropyl) carbodiimide hydrochloride. Can be amidated with amines;
Acidic functional groups can be protected in the form of an ester formed with an easily cleavable ester such as, for example, a benzyl or tert-butyl ester, or an ester known in peptide chemistry.

Reactions a) to k) can be carried out, for example, as shown below.
a) The above-mentioned products can be subjected to esterification reactions which can be carried out on the possible carboxyl functions, if desired, according to conventional methods known to those skilled in the art.
b) The conversion of ester functions into acidic functions possible in the products described above is optionally carried out under normal conditions known to the person skilled in the art, in particular sodium hydroxide in alcoholic solvents such as methanol, for example. Alternatively, it can be carried out by acid or alkali hydrolysis using potassium hydroxide or hydrochloric acid or sulfuric acid.
The saponification reaction can be carried out according to a conventional method known to those skilled in the art, for example, in a solvent such as methanol or ethanol, dioxane or dimethoxyethane, in the presence of sodium hydroxide or potassium hydroxide.

c) Possible alkylthio groups in the above products are optionally obtained under normal conditions known to the person skilled in the art, for example with peracids such as peracetic acid or metachloroperbenzoic acid, or with ozone, oxone or peroxygen. Sodium iodate can be used to convert to the corresponding sulfoxide or sulfone functionality in a solvent such as methylene chloride or dioxane at room temperature.
The production of sulfoxide functional groups can be facilitated by equimolar mixtures of products containing alkylthio groups with reagents such as, in particular, peracids.
The production of sulfone functional groups can be facilitated by a mixture of products containing alkylthio groups and an excess of a reagent such as peracid.
d) The conversion reaction of the ketone function to the oxime is carried out under normal conditions known to the person skilled in the art, for example in the presence of optionally O-substituted hydroxylamine, for example in alcohols such as ethanol at room temperature. Or by heating.
e) Possible free or esterified carboxyl functions in the above products can be reduced to alcohol functions by methods known to those skilled in the art if desired: possible esterified carboxyl functions Can be reduced to the alcohol function, if desired, by methods known to those skilled in the art and in particular with lithium aluminum hydride, for example in a solvent such as tetrahydrofuran or dioxane or ethyl ether.

The free carboxyl functionality possible in the products described above can be reduced to the alcohol functionality, if desired, especially using borohydride.
f) possible alkoxy functional groups in the above-mentioned products, for example in particular methoxy, are optionally brominated using normal conditions known to the person skilled in the art, for example with boron tribromide in a solvent such as methylene chloride. It can be converted to a hydroxyl functional group using pyridine hydroacid or pyridine hydrochloride or under reflux using hydrobromic acid or hydrochloric acid in water or trifluoroacetic acid.
g) possible alcohol functions in the above-mentioned compounds, if desired, by oxidation under normal conditions known to the person skilled in the art, for example by the action of manganese oxide producing aldehydes or by the action of Jones reagents producing acids. Can be converted to aldehydes or acidic functional groups.
h) Possible nitrile functional groups in the above-mentioned compounds, if desired, under the usual conditions known to the person skilled in the art, for example as described in the following reference: J. Organometallic Chemistry., 33, 337 (1971) KOZIMA S. et al. Can be converted to tetrazolyl by cycloaddition of a metal azide, such as sodium azide or trialkyltin azide, with a nitrile function, as shown in the method described.

The conversion reaction of carbamate to urea, and in particular the conversion reaction of sulfonyl carbamate to sulfonyl urea, can be carried out in the presence of a suitable amine in a refluxing solvent such as toluene.
It will be appreciated that the reactions described above may be carried out as described or, where appropriate, according to other conventional methods known to those skilled in the art.

i) Removal of protecting groups, eg protecting groups as indicated above, under the usual conditions known to the person skilled in the art, in particular like hydrochloric acid, benzenesulfonic acid or para-toluenesulfonic acid, formic acid or trifluoroacetic acid It can be carried out by acid hydrolysis carried out with an acid, or alternatively by hydrogenation using a catalyst.
The phthalimide group can be removed with hydrazine.
A list of various protecting groups that can be used is described, for example, in the patent BF2499995.
j) The above-mentioned compounds can optionally be subjected to a chlorination reaction, for example with an inorganic or organic acid, or with an inorganic or organic base, according to conventional methods known to those skilled in the art: For example, it can be carried out in the presence of hydrochloric acid and alternatively in the presence of tartaric acid, citric acid or metasulfonic acid, for example in an alcohol such as ethanol or methanol.
k) Possible optically active forms of the above-mentioned compounds can be prepared by resolution of racemic mixtures according to conventional methods known to those skilled in the art.
Such an above-mentioned reaction is demonstrated in the manufacture example described below.

The compounds of formula (I) as defined above, and also their addition salts with acids, have advantageous pharmacological properties, especially due to their kinase inhibitory properties described above. Because certain kinase proteins have a central role in the initiation, development, and completion of cell cycle events, molecules that inhibit such kinases limit undesirable cell growth as observed in cancer And can mediate in the prevention, regulation or treatment of neurodegenerative diseases such as Alzheimer's disease or neuronal apoptosis.
The compounds of the present invention are more particularly useful for the prevention, regulation or treatment of diseases requiring anti-angiogenic activity.
The compounds of the present invention are particularly useful for the treatment of tumors.
Accordingly, the compounds of the present invention can also increase the therapeutic effects of commonly used anti-tumor agents. Accordingly, the compounds of formula (I) of the present invention more particularly have anti-angiogenic properties.
These properties show justification for its therapeutic use, and the subject of the invention is in particular a compound of formula (I) as defined above, as a medicament, wherein the compound of formula (I) is All possible racemic, enantiomeric or diastereoisomeric forms, and also the formula (with pharmaceutically acceptable inorganic and organic acids or with pharmaceutically acceptable inorganic and organic bases) It may be an addition salt of the product of I).

  Accordingly, one subject of the present invention is more particularly a compound as defined by formula (IA), (IAa) or (IAb) as a medicament, said formula (IA), (IAa) or (IAb) ) In any possible racemic, enantiomeric or diastereoisomeric form thereof, and also with pharmaceutically acceptable inorganic and organic acids or with pharmaceutically acceptable inorganic bases and An addition salt of the product of formula (IA), (IAa) or (IAb) with an organic base.

One subject of the present invention is more particularly the pharmaceutical, the compounds described below in the examples, and in particular the products corresponding to the following formula:
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-methylamide 2- ( 1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-ethylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-isopropylamide 2- (1H -Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenethylamide 2- (1H -Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-morpho Noamido 2-(1H-indazol-3-yl)-1H-benzoimidazole-5-carboxylic acid N-(N'-methyl - piperazino) amide

2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-pyrrolidinoamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- ( Isobutyl) amide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (cyclohexylmethyl) amide 2- (1H-indazol-3-yl) -1H-benzimidazole-5 Carboxylic acid N- (2-furfuryl) amide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide methyl 2- (1H-indazol-3-yl) -3H-benzimidazole-5-carboxylate 5,6-dimethyl-2- (1H-indazole-3- Yl) -1H-benzimidazole 5-methoxy-2- (1H-indazol-3-yl) -1H-benzimidazole

2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 5-bromo-2- (1H-indazol-3-yl) -3H-benzimidazole 2- (5-ethoxy-2H- Pyrazol-3-yl) -1H-benzimidazole-4-carboxylic acid 5,6-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -1H-benzimidazole 5,6-dimethyl-2- (5-thiophen-2-yl-2H-pyrazol-3-yl) -1H-benzimidazole 2- (4-bromo-2H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole 2- (5-ethyl-2H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole 2- (5-ethyl-2H-pyrazol-3-yl) -4, -Ethylenedioxy-1H-benzimidazole 2- (5-ethyl-2H-pyrazol-3-yl) -5-methoxy-1H-benzimidazole 2- (5-ethyl-2H-pyrazol-3-yl) -4 -Hydroxy-1H-benzimidazole 2- (5-ethyl-2H-pyrazol-3-yl) -5-bromo-1H-benzimidazole

2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4- (aminosulfonyl) benzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-Bromobenzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4- (methanesulfonyl) benzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole -5-carboxylic acid 4-nitrobenzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-methylbenzylamide 2- (1H-indazol-3-yl) -1H- Benzimidazole-5-carboxylic acid (6-chloropyridin-3-ylmethyl) amide 2 (1H-Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (2,3-dihydrobenzofuran-5-ylmethyl) amide 2- (1H-indazol-3-yl) -1H-benzimidazole-5 -Carboxylic acid 2- (methylsulfanyl) benzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (benzo [b] thiophen-3-ylmethyl) amide 2- (1H-indazole) -3-yl) -1H-benzimidazole-5-carboxylic acid 3-methylbenzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-chlorobenzylamide 2- (1H -Indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 2- (me Rusurufaniru) benzylamide.

One subject of the present invention is more particularly a pharmaceutical compound of formula (I) as defined above corresponding to the following formula:
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-methylamide 2- ( 1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-ethylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-isopropylamide 2- (1H -Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenethylamide 2- (1H -Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-morpho Noamido 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (N′-methyl-piperazino) amide 2- (1H-indazol-3-yl) -1H-benzimidazole 5-Carboxylic acid N-pyrrolidinoamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (isobutyl) amide 2- (1H-indazol-3-yl) -1H- Benzimidazole-5-carboxylic acid N- (cyclohexylmethyl) amide 2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid N- (2-furfuryl) amide 2- (1H-indazole- 3-yl) -1H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide

5-Methoxy-2- (1H-indazol-3-yl) -1H-benzimidazole 2- (5-ethyl-2H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole 2- (5 -Ethyl-2H-pyrazol-3-yl) -4,5-ethylenedioxy-1H-benzimidazole 2- (5-ethyl-2H-pyrazol-3-yl) -5-methoxy-1H-benzimidazole 2- (5-Ethyl-2H-pyrazol-3-yl) -4-hydroxy-1H-benzimidazole 2- (5-Ethyl-2H-pyrazol-3-yl) -5-bromo-1H-benzimidazole.

One subject of the present invention is more particularly a pharmaceutical compound of formula (I) as defined above, corresponding to the following formula:
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4- (aminosulfonyl) benzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-Bromobenzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4- (methanesulfonyl) benzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole -5-carboxylic acid 4-nitrobenzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-methylbenzylamide 2- (1H-indazol-3-yl) -1H- Benzimidazole-5-carboxylic acid (6-chloropyridin-3-ylmethyl) amide 2 (1H-Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (2,3-dihydrobenzofuran-5-ylmethyl) amide 2- (1H-indazol-3-yl) -1H-benzimidazole-5 -Carboxylic acid 2- (methylsulfanyl) benzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (benzo [b] thiophen-3-ylmethyl) amide 2- (1H-indazole) -3-yl) -1H-benzimidazole-5-carboxylic acid 3-methylbenzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-chlorobenzylamide 2- (1H -Indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 2- (me Rusurufaniru) benzylamide.

The invention also includes as active ingredient at least one compound of formula (I) as defined above, or a pharmaceutically acceptable salt of the compound or a prodrug of the compound, and, where appropriate, a pharmaceutically acceptable. It relates to a pharmaceutical composition comprising a carrier.
Accordingly, the present invention encompasses a pharmaceutical composition comprising as active ingredient at least one medicament as defined above.
Such pharmaceutical compositions of the present invention may also contain, if appropriate, the active ingredients of other cytostatic pharmaceutical products such as, for example, products based on taxol, cisplatin, DNA intercalating agents and the like. it can.
These pharmaceutical compositions can be administered orally, parenterally, ie by topical application to the skin and mucosa, or topically by intravenous or intramuscular injection.

These compositions may be solid or liquid and may be in any pharmaceutical form commonly used in human medicine, such as single or sugar-coated tablets, pills, troches, gel capsules, It may be in the form of drops, granules, injectable preparations, ointments, creams or gels; these are manufactured according to the usual methods. The active ingredients are usually used in these pharmaceutical compositions such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, water-soluble or water-insoluble vehicles, fatty substances derived from animals or plants, paraffin Derivatives, glycols, and various wetting agents, dispersing agents, emulsifiers or preservatives can be incorporated into the composition.
Usual dosages that may vary depending on the compound used, the individual being treated and the disease being considered may be, for example, 0.05 to 5 g per day for adults, or preferably 0.1 to 2 g per day. .

  The subject of the present invention is also the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt of these compounds, for the manufacture of a pharmaceutical product intended to inhibit kinase protein activity. is there.

The subject of the present invention is also the use of a compound of formula (I) as defined above for the manufacture of a medicament for the treatment or prevention of diseases characterized by dysregulation of kinase protein activity.
Such medicaments may be intended for the treatment or prevention of diseases, particularly in mammals.

The subject of the present invention is also the use as defined above, wherein the kinase protein is a tyrosine kinase protein.
The subject of the invention is also defined above, wherein the kinase protein is selected from the following groups: FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, flt-1, IGF-1R, KDR, PDGFR, tie2 and VEGFR Is use.

  The subject of the present invention is also the use as defined above, wherein the kinase protein is KDR.

  The subject of the present invention is also the use as defined above, wherein the kinase protein is tie2.

The subject of the present invention is also the use as defined above, wherein the kinase protein is involved in cell culture.
The subject of the present invention is also the use as defined above, wherein the kinase protein is a kinase protein in a mammal.

  The subject of the present invention is in particular the following groups: vascular proliferation abnormalities, fibrotic disorders, "mesangial" cell proliferation abnormalities, metabolic abnormalities, allergies, asthma, thrombosis, nervous system diseases, retinopathy, psoriasis, rheumatoid Use of a product of formula (I) as defined above for the manufacture of a pharmaceutical product for the treatment or prevention of diseases selected from arthritis, diabetes, muscle degeneration and cancer.

  The subject of the invention more particularly comprises the following groups: vascular proliferative disorders, fibrotic disorders, "mesangial" cell proliferative disorders, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration and cancer Use of a product of formula (I) as defined above for the manufacture of a pharmaceutical product for the treatment or prevention of a selected disease.

The subject of the present invention is more particularly intended for the treatment of diseases in oncology, and in particular for the treatment of cancer, for the manufacture of pharmaceutical products for the prevention or treatment of diseases involving uncontrolled angiogenesis. The use of a product of formula (I) as defined above for the manufacture of a pharmaceutical product.
Of these cancers, treatment of solid tumors and cancers that are resistant to cytotoxic drugs are important.
Among these cancers, breast cancer, stomach cancer, ovarian cancer, colon cancer, lung cancer, brain tumor, laryngeal cancer, lymphatic cancer, urogenital tract cancer including bladder and prostate, bone cancer As well as the treatment of pancreatic cancer, and more particularly the treatment of breast, colon, or lung cancer.

The subject of the present invention is also the use of a product of formula (I) as defined above for the manufacture of a pharmaceutical product for cancer chemotherapy.
Such pharmaceutical products intended for cancer chemotherapy may be used alone or in combination.

The products of the present patent application may in particular be administered alone, in combination with chemotherapy or radiation therapy, or for example in combination with other therapeutic agents.
Such a therapeutic agent may be a commonly used antitumor agent.
Examples of kinase inhibitors include butyrolactone, flavopiridol, and 2- (2-hydroxyethylamino) -6-benzylamino-9-methylpurine (also known as olomucine).

The subject of the present invention is also a compound of formula (I) as defined above as a KDR inhibitor.
The subject of the present invention is also a compound of formula (I) as defined above as a tie2 inhibitor.

The compounds described in the following three tables entitled Tables I, II and III form part of the present invention, and these products, and also the compounds described in the experimental section, illustrate the present invention. The compound of formula (I) is not intended to limit the present invention.

ここで、Ｘは水素、ハロゲンまたは上記で定義されたアルコキシを示す。

Here, X represents hydrogen, halogen or alkoxy as defined above.

式中、ＮＲ’Ｒは、上記で定義されるＮＹ１Ｙ２を示す。

In the formula, NR′R represents NY1Y2 as defined above.

式中、Ｘは、水素、アルキニル、または場合により置換されているＮＨＣＯＣＨ２Ｐｈを示す。

Wherein X represents hydrogen, alkynyl, or optionally substituted NHCOCH2Ph.

Experimental section General methods of LC / MS purification:
A Waters FractionLynx system was used and the separation was performed on a Waters Symmetry column (C18, 5
elution is performed on a linear gradient of acetonitrile (including 0.07% TFA (v / v)) in water (containing 0.07% TFA (v / v)). The acetonitrile / TFA was increased from 5% to 95% (v / v) in 8 minutes at a flow rate of 10 ml / min and then at acetonitrile / TFA 95% for 2 minutes. The product was injected dissolved in DMSO and recovered according to its molecular weight detection.
Chemical shifts in NMR are given in ppm.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸ベンジルアミドは、以下の方法で製造できる。
ジメチルホルムアミド０.２ｍｌ中のＨＢＴＵ２７.３ｍｇの溶液を、約２０℃で、無水ジメチルホルムアミド０.４２ｍｌ中の２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇの溶液に加えた。約２０℃で１時間攪拌後、ベンジルアミン１５.７ｍｌを加え、続けてジメチルホルムアミド０.３２ｍｌに溶解したＮ,Ｎ−ジイソプロピルエチルアミン１２.４ｍｌを加えた。約２０℃で２０時間後に、反応溶媒を約４０℃で減圧下で濃縮した。得られた粗残留物をＤＭＳＯに溶解し、分取ＬＣ／ＭＳで精製した。所望の生成物を含む画分を合わせて、約４０℃で減圧下で濃縮した。このようにして、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸ベンジルアミド２０ｍｇをクリーム色粉末形態で得、その特性は以下のとおりであった：
ＬＣ／ＭＳ 保持時間＝２.８６分
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸は、以下の方法で製造できる：
メタ亜硫酸水素ナトリウム１.３ｇ、および３,４−ジアミノ安息香酸１.０４ｇを、約２０℃で、ジメチルホルムアミド１０ｍｌ中の１Ｈ−インダゾール−３−カルボキシアルデヒド１ｇの溶液に加えた。反応混合物を１時間還流し、次いで約２０℃に冷却し、ジクロロメタンで希釈し、そしてこの混合物を濾過した。回収した濾液を減圧下で濃縮した。得られた褐色ラッカー（３４０ｍｇ）を分取ＬＣ／ＭＳで精製した。このようにして、５,６−ジメチル−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール１３８.８ｍｇをベージュ色粉末の形態で得た。 [Example 1]
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzylamide

2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzylamide can be produced by the following method.
A solution of 27.3 mg of HBTU in 0.2 ml of dimethylformamide was added at about 20 ° C. to 20 mg of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid in 0.42 ml of anhydrous dimethylformamide. Added to the solution. After stirring at about 20 ° C. for 1 hour, 15.7 ml of benzylamine was added, followed by 12.4 ml of N, N-diisopropylethylamine dissolved in 0.32 ml of dimethylformamide. After 20 hours at about 20 ° C., the reaction solvent was concentrated at about 40 ° C. under reduced pressure. The resulting crude residue was dissolved in DMSO and purified by preparative LC / MS. Fractions containing the desired product were combined and concentrated at about 40 ° C. under reduced pressure. In this way 20 mg of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzylamide was obtained in the form of a cream powder, the properties of which were as follows:
LC / MS Retention time = 2.86 minutes 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid can be prepared by the following method:
1.3 g sodium metabisulfite and 1.04 g 3,4-diaminobenzoic acid were added at about 20 ° C. to a solution of 1 g 1H-indazole-3-carboxaldehyde in 10 ml dimethylformamide. The reaction mixture was refluxed for 1 hour, then cooled to about 20 ° C., diluted with dichloromethane, and the mixture was filtered. The collected filtrate was concentrated under reduced pressure. The resulting brown lacquer (340 mg) was purified by preparative LC / MS. There were thus obtained 138.8 mg of 5,6-dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole in the form of a beige powder.

1H-indazole-3-carboxaldehyde can be produced by the following method:
A solution of 2.27 g of (1H-indazol-3-yl) methanol in 220 ml of 1,2-dimethoxyethane was added to 13.32 g of manganese dioxide. After 1 hour at about 20 ° C., the reaction mixture was refluxed for 15 minutes. After cooling to about 20 ° C., the reaction solvent was filtered through a sintered funnel packed with celite. The collected filtrate was concentrated at about 40 ° C. under reduced pressure. In this way 2.02 g of 1H-indazole-3-carboxaldehyde was obtained in the form of a yellow powder, the properties of which were as follows:
1H NMR, DMSO d6, 400 MHz: 7.40 ppm (triplet, 1H); 7.55 ppm (triplet,
1H); 7.75 ppm (doublet, 1H); 8.18 ppm (doublet, 1H); 10.23 ppm (singlet, 1H); 14.2 ppm (multiplet, 1H).

(1H-indazol-3-yl) methanol can be produced by the following method:
3.2 g of lithium aluminum hydride was added in several portions to a solution of 7.08 g of methyl 3-indazolecarboxylate in 80 ml of tetrahydrofuran and cooled to about 0 ° C. in an ice bath. After 4 hours at about 0 ° C., 1.6 g of lithium aluminum hydride was added. After 2 hours at about 0 ° C., the reaction solvent was subsequently treated with 6 ml of water and then with 6 ml of 1N aqueous sodium hydroxide solution and finally with 18 ml of water. The reaction mixture was filtered through filter paper and then the aqueous filtrate was extracted with dichloromethane. The collected organic fractions were combined, dried over magnesium sulfate, and concentrated at about 40 ° C. under reduced pressure. 3.15 g of (1H-indazol-3-yl) methanol was obtained in the form of an off-white powder, the characteristics of which were as follows:
1H NMR, DMSO d6, 400 MHz: 4.80 ppm (doublet, 2H); 5.25 ppm (triplet, 1H); 7.15 ppm (triplet, 1H); 7.35 ppm (triplet, 1H); 7.51 ppm (doublet, 1H); 7.87 ppm (doublet, 1H); 12.81 ppm (multiplet, 1H).

Methyl 3-indazolecarboxylate can be produced by the following method:
0.5 ml of concentrated sulfuric acid (95%) was added dropwise at about 20 ° C. to a solution of 9.13 g of 3-indazolecarboxylic acid in 100 ml of methanol. After refluxing for 20 hours, the reaction solvent was concentrated at about 40 ° C. under reduced pressure. The resulting water soluble residue was extracted with dichloromethane. The organic phases were combined, washed with water until neutral, dried over magnesium sulfate and then concentrated at about 40 ° C. under reduced pressure. The resulting yellow powder was washed with ethyl ether. A white powder was obtained. The filtrate was concentrated under reduced pressure to give a yellow powder. This yellow powder was washed again with ethyl ether to obtain a white powder. The yellow filtrate was concentrated three times under reduced pressure, and the recovered yellow powder itself was also washed with ethyl ether. All fractions of white powder were combined. In this way 7.08 g of methyl 3-indazolecarboxylate was obtained in the form of a white powder.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−メチルアミドは、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジルアミド（実施例１）の製造について記載した手順に従って製造できる：
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇ、およびメチルアミン溶液（テトラヒドロフラン中で２Ｍ）７１.８μｌを出発物質として、所望の生成物１４.８ｍｇを得た。 [Example 2]
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-methylamide

2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-methylamide is N-benzyl 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid Can be prepared according to the procedure described for the preparation of the amide (Example 1):
Starting from 20 mg of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 71.8 μl of methylamine solution (2M in tetrahydrofuran), 14.8 mg of the desired product are obtained. It was.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−エチルアミドは、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジルアミド（実施例１）の製造について記載した手順に従って製造できる：
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇ、およびエチルアミン溶液（水中で３３％）１９.４ｍｌを出発物質として、２
−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−エチルアミド１４.８ｍｇを得た。 Example 3
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-ethylamide

2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-ethylamide is N-benzyl 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid Can be prepared according to the procedure described for the preparation of the amide (Example 1):
Starting with 20 mg of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 19.4 ml of ethylamine solution (33% in water), 2
-(1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-ethylamide (14.8 mg) was obtained.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−イソプロピルアミドは、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジルアミド（実施例１）の製造について記載した手順に従って製造できる：
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇ、およびイソプロピルアミン１２.３ｍｌを出発物質として、２−（１Ｈ−イン
ダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−イソプロピルアミド１６.５ｍｇを得た。 Example 4
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-isopropylamide

2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-isopropylamide is 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- Can be prepared according to the procedure described for the preparation of benzylamide (Example 1):
Starting from 20 mg of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 12.3 ml of isopropylamine, 2- (1H-indazol-3-yl) -1H-benzimidazole 16.5 mg of -5-carboxylic acid N-isopropylamide was obtained.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−フェニルアミドは、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジルアミド（実施例１）の製造について記載した手順に従って製造できる：
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇ、およびアニリン１３.１ｍｌを出発物質として、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−フェニルアミド１４.１ｍｇを白色粉末の形態で得た。 Example 5
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenylamide

2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenylamide is 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- It can be prepared according to the procedure described for the preparation of benzylamide (Example 1):
Starting from 20 mg of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 13.1 ml of aniline, 2- (1H-indazol-3-yl) -1H-benzimidazole- 14.1 mg of 5-carboxylic acid N-phenylamide was obtained in the form of a white powder.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−フェネチルアミドは、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジルアミド（実施例１）の製造について記載した手順に従って製造できる：
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇ、およびフェネチルアミン１８ｍｌを出発物質として、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５カルボン酸Ｎ−フェネチルアミド１７.
７ｍｇを白色粉末の形態で得た。 Example 6
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenethylamide

2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenethylamide is obtained from 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- It can be prepared according to the procedure described for the preparation of benzylamide (Example 1):
Starting from 20 mg of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 18 ml of phenethylamine, 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxyl Acid N-phenethylamide 17.
7 mg was obtained in the form of a white powder.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−モルホリノアミドは、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジルアミド（実施例１）の製造について記載した手順に従って製造できる：
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇ、およびモルホリン１２.５ｍｌを出発物質として、２−（１Ｈ−インダゾール
−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−モルホリノアミド１８.
６ｍｇを淡黄色粉末の形態で得た。 Example 7
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-morpholinoamide

2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-morpholinoamide is 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- It can be prepared according to the procedure described for the preparation of benzylamide (Example 1):
Starting from 20 mg of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 12.5 ml of morpholine, 2- (1H-indazol-3-yl) -1H-benzimidazole- 5-Carboxylic acid N-morpholinoamide 18.
6 mg was obtained in the form of a pale yellow powder.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−（Ｎ’−メチル−ピペラジノ）アミドは、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジルアミド（実施例１）の製造について記載した手順に従って製造できる：
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇ、およびＮ−メチルピペラジン１５.９ｍｌを出発物質として、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−（Ｎ’−メチル−ピペラジノ）アミド１６.１ｍｇを黄色油状物質として得た。 Example 8
2- (1H-Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (N′-methyl-piperazino) amide

2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (N′-methyl-piperazino) amide is 2- (1H-indazol-3-yl) -1H-benzimidazole Can be prepared according to the procedure described for the preparation of -5-carboxylic acid N-benzylamide (Example 1):
Starting from 20 mg of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 15.9 ml of N-methylpiperazine, 2- (1H-indazol-3-yl) -1H- 16.1 mg of benzimidazole-5-carboxylic acid N- (N′-methyl-piperazino) amide was obtained as a yellow oil.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ピロリジノアミドは、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジルアミド（実施例１）の製造について記載した手順に従って製造できる：
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇ、およびピロリジン１２ｍｌを出発物質として、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５カルボン酸Ｎ−ピロリジノアミド１７.７ｍｇを淡黄色粉末の形態で得た。 Example 9
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-pyrrolidinoamide

2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-pyrrolidinoamide is 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N Can be prepared according to the procedure described for the preparation of benzylamide (Example 1):
Starting from 20 mg of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 12 ml of pyrrolidine, 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxyl 17.7 mg of acid N-pyrrolidinoamide are obtained in the form of a pale yellow powder.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−（イソブチル）アミドは、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジルアミド（実施例１）の製造について記載した手順に従って製造できる：
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇ、およびイソブチルアミン１４.６ｍｌを出発物質として、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−（イソブチル）アミド７.６ｍｇを淡黄色粉末の形態で得た。 Example 10
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (isobutyl) amide

2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (isobutyl) amide is 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid It can be prepared according to the procedure described for the preparation of N-benzylamide (Example 1):
Starting from 20 mg of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 14.6 ml of isobutylamine, 2- (1H-indazol-3-yl) -1H-benzimidazole 7.6 mg of -5-carboxylic acid N- (isobutyl) amide was obtained in the form of a pale yellow powder.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−（シクロヘキシルメチル）アミドは、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジルアミド（実施例１）の製造について記載した手順に従って製造できる：
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇ、およびシクロヘキシルメチルアミン１８.７ｍｌを出発物質として、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−（シクロヘキシルメチル）アミド１６.１ｍｇを白色粉末の形態で得た。 Example 11
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (cyclohexylmethyl) amide

2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (cyclohexylmethyl) amide is 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid. It can be prepared according to the procedure described for the preparation of the acid N-benzylamide (Example 1):
Starting from 20 mg of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 18.7 ml of cyclohexylmethylamine, 2- (1H-indazol-3-yl) -1H-benzo 16.1 mg of imidazole-5-carboxylic acid N- (cyclohexylmethyl) amide was obtained in the form of a white powder.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−（２−フルフリル）アミドは、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジルアミド（実施例１）の製造について記載した手順に従って製造できる：
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇ、および２−フルフリルアミン１３.３ｍｌを出発物質として、２−（１Ｈ−イ
ンダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−（２−フルフリル）アミド１４.８ｍｇを白色粉末の形態で得た。 Example 12
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (2-furfuryl) amide

2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (2-furfuryl) amide is 2- (1H-indazol-3-yl) -1H-benzimidazole-5 Can be prepared according to the procedure described for the preparation of carboxylic acid N-benzylamide (Example 1):
Starting from 20 mg of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 13.3 ml of 2-furfurylamine, 2- (1H-indazol-3-yl) -1H- 14.8 mg of benzimidazole-5-carboxylic acid N- (2-furfuryl) amide are obtained in the form of a white powder.

２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジル−Ｎ−メチルアミドは、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジルアミド（実施例１）の製造について記載した手順に従って製造できる：
２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸２０ｍｇ、およびＮ−メチルベンジルアミン１８.６ｍｌを出発物質として、２−（１Ｈ
−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール−５−カルボン酸Ｎ−ベンジル−Ｎ−メチルアミド７.３ｍｇを淡黄色粉末の形態で得た。 Example 13
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide

2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide is 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid. It can be prepared according to the procedure described for the preparation of the acid N-benzylamide (Example 1):
Starting from 20 mg of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 18.6 ml of N-methylbenzylamine, 2- (1H
-Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide 7.3 mg was obtained in the form of a pale yellow powder.

メチル２−（１Ｈ−インダゾール−３−イル）−３Ｈ−ベンゾイミダゾール−５−カルボキシレートは、以下の方法で製造できる：
ニトロベンゼン１０ｍｌ中の、１Ｈ−インダゾール−３−カルボキシアルデヒド０.１ｇおよびメチル３,４−ジアミノベンゾエート１１３.７ｍｇの混合物を、３時間４５分の間、約１４５℃で維持した。約２０℃に冷却後、反応混合物をＳＰＥ（ＳＣＸ相５ｇ、メタノールで処理および洗浄、２Ｎアンモニア性メタノール溶液で抽出）上で精製した。次いで分離中に回収されたアンモニア性溶液を、減圧下、約４０℃で濃縮した。橙色ラッカー１９８.３ｍｇを得、これを分取ＬＣ／ＭＳで精製した。このようにして、メチル２−（１Ｈ−インダゾール−３−イル）−３Ｈ−ベンゾイミダゾール−５−カルボキシレート４２.７ｍｇをベージュ色粉末の形態で得、その特性は以下のとおりであった：
1H NMR, DMSO d6, 400 MHz: 3.95 ppm (シングレット, 3H); 7.40 ppm (トリプレット,
1H); 7.55 ppm (トリプレット, 1H); 7.75 ppm (ダブレット, 1H); 7.77 ppm (ダブレット, 1H); 7.95 ppm (ダブレット, 1H); 8.57 ppm (ダブレット, 1H); 13.85 ppm (マルチプレット, 1H). Example 14
Methyl 2- (1H-indazol-3-yl) -3H-benzimidazole-5-carboxylate

Methyl 2- (1H-indazol-3-yl) -3H-benzimidazole-5-carboxylate can be prepared by the following method:
A mixture of 0.1 g of 1H-indazole-3-carboxaldehyde and 113.7 mg of methyl 3,4-diaminobenzoate in 10 ml of nitrobenzene was maintained at about 145 ° C. for 3 hours and 45 minutes. After cooling to about 20 ° C., the reaction mixture was purified on SPE (SCX phase 5 g, treated and washed with methanol, extracted with 2N ammoniacal methanol solution). The ammoniacal solution recovered during the separation was then concentrated at about 40 ° C. under reduced pressure. 198.3 mg of orange lacquer was obtained, which was purified by preparative LC / MS. In this way 42.7 mg of methyl 2- (1H-indazol-3-yl) -3H-benzimidazole-5-carboxylate are obtained in the form of a beige powder, the characteristics of which are as follows:
1H NMR, DMSO d6, 400 MHz: 3.95 ppm (singlet, 3H); 7.40 ppm (triplet,
7.55 ppm (doublet, 1H); 7.75 ppm (doublet, 1H); 7.77 ppm (doublet, 1H); 7.95 ppm (doublet, 1H); 8.57 ppm (doublet, 1H); 13.85 ppm (multiplet, 1H) ).

５,６−ジメチル−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾールは、メチル２−（１Ｈ−インダゾール−３−イル）−３Ｈ−ベンゾイミダゾール−５−カルボキシレート（実施例１４）の製造について記載した手順に従って製造できる：
ニトロベンゼン１０ｍｌ中の、１Ｈ−インダゾール−３−カルボキシアルデヒド２００ｍｇ、および４,５−ジメチル−１,２−フェニレンジアミン１７７ｍｇを出発物質として、５,６−ジメチル−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール１５.９ｍｇを暗赤色粉末の形態で得、その特性は以下のとおりであった：
1H NMR, DMSO d6, 400 MHz: 2.60 ppm (シングレット, 6H); 7.42 ppm (トリプレット,
1H); 7.53 ppm (シングレット, 2H); 7.58 ppm (トリプレット, 1H); 7.78 ppm (ダブレット, 1H); 8.52 ppm (ダブレット, 1H); 14.05 ppm (マルチプレット, 1H). Example 15
5,6-Dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole

5,6-Dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole is methyl 2- (1H-indazol-3-yl) -3H-benzimidazole-5-carboxylate (Example 14). Can be produced according to the procedure described for the production of:
Starting with 200 mg of 1H-indazole-3-carboxaldehyde and 177 mg of 4,5-dimethyl-1,2-phenylenediamine in 10 ml of nitrobenzene, 5,6-dimethyl-2- (1H-indazol-3-yl) ) -15.9 mg of 1H-benzimidazole was obtained in the form of a dark red powder, the properties of which were as follows:
1H NMR, DMSO d6, 400 MHz: 2.60 ppm (singlet, 6H); 7.42 ppm (triplet,
7.53 ppm (singlet, 2H); 7.58 ppm (triplet, 1H); 7.78 ppm (doublet, 1H); 8.52 ppm (doublet, 1H); 14.05 ppm (multiplet, 1H).

5,6-Dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole can also be prepared according to the following procedure:
389 mg sodium metabisulfite was added at about 20 ° C. to a solution of 300 mg 1H-indazole-3-carboxaldehyde and 279 mg 4,5-dimethyl-1,2-phenylenediamine in 3 ml dimethylformamide. The reaction mixture is refluxed for 4 hours,
It was then cooled to about 20 ° C. and filtered through filter paper. The collected filtrate was concentrated under reduced pressure. The resulting brown lacquer (340 mg) was purified by preparative LC / MS. There were thus obtained 138.8 mg of 5,6-dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole in the form of a beige powder.

５−メトキシ−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾールは、メチル２−（１Ｈ−インダゾール−３−イル）−３Ｈ−ベンゾイミダゾール−５−カルボキシレート（実施例１４）の製造について記載した手順に従って製造できる：
ニトロベンゼン１０ｍｌ中の１Ｈ−インダゾール−３−カルボキシアルデヒド２００ｍｇおよび４−メトキシ−１,２−フェニレンジアミンジヒドロクロリド２７４.４ｍｇを出発物質として、５−メトキシ−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール４５.６ｍｇを明褐色粉末の形態で得、その特性は以下のとおりであった：
1H NMR, DMSO d6, 400 MHz: 3.90 ppm (シングレット, 3H); 7.00 ppm (ダブレット, 1H); 7.18 ppm (ダブレット, 1H); 7.40 ppm (トリプレット, 1H); 7.55 ppm (トリプレット, 1H); 7.64 ppm (ダブレット, 1H); 7.73 ppm (ダブレット, 1H); 8.52 ppm (ダブレット, 1H); 13.91 ppm (マルチプレット, 1H). Example 16
5-Methoxy-2- (1H-indazol-3-yl) -1H-benzimidazole

5-Methoxy-2- (1H-indazol-3-yl) -1H-benzimidazole was obtained from methyl 2- (1H-indazol-3-yl) -3H-benzimidazole-5-carboxylate (Example 14). Can be produced according to the procedure described for production:
Starting from 200 mg of 1H-indazole-3-carboxaldehyde and 274.4 mg of 4-methoxy-1,2-phenylenediamine dihydrochloride in 10 ml of nitrobenzene, 5-methoxy-2- (1H-indazol-3-yl)- 45.6 mg of 1H-benzimidazole was obtained in the form of a light brown powder, the characteristics of which were as follows:
1H NMR, DMSO d6, 400 MHz: 3.90 ppm (singlet, 3H); 7.00 ppm (doublet, 1H); 7.18 ppm (doublet, 1H); 7.40 ppm (triplet, 1H); 7.55 ppm (triplet, 1H); 7.64 ppm (doublet, 1H); 7.73 ppm (doublet, 1H); 8.52 ppm (doublet, 1H); 13.91 ppm (multiplet, 1H).

２−（１Ｈ−インダゾール−３−イル）−３Ｈ−ベンゾイミダゾール−４−カルボン酸は、メチル２−（１Ｈ−インダゾール−３−イル）−３Ｈ−ベンゾイミダゾール−５−カルボキシレート（実施例１４）の製造について記載した手順に従って製造できる：
ニトロベンゼン１０ｍｌ中の１Ｈ−インダゾール−３−カルボキシアルデヒド２３７ｍｇ、および２,３−ジアミノ安息香酸ヒドロクロリド３０５.５ｍｇを出発物質として、２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール酸の２−（１Ｈ−インダゾール−３−イル）−３Ｈ−ベンゾイミダゾール−４−カルボン酸５−メトキシアミド２０.５ｍｇを、ベージュ色粉末の形態で得、その特性は以下のとおりであった：
1H NMR, DMSO d6, 400 MHz: 7.40 ppm (トリプレット, 1H); 7.42 ppm (トリプレット,
1H); 7.55 ppm (トリプレット, 1H); 7.72 ppm (ダブレット, 1H); 7.90 ppm (ダブレット, 1H); 8.02 ppm (ダブレット, 1H); 8.52 ppm (ダブレット, 1H); 13.68 ppm (マルチプレット, 1H). Example 17
2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid

2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid is methyl 2- (1H-indazol-3-yl) -3H-benzimidazole-5-carboxylate (Example 14). Can be produced according to the procedure described for the production of:
Starting from 237 mg of 1H-indazole-3-carboxaldehyde and 105.5 mg of 2,3-diaminobenzoic acid hydrochloride in 10 ml of nitrobenzene, starting material of 2- (1H-indazol-3-yl) -1H-benzimidazolic acid 20.5 mg of 2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 5-methoxyamide was obtained in the form of a beige powder, the properties of which were as follows:
1H NMR, DMSO d6, 400 MHz: 7.40 ppm (triplet, 1H); 7.42 ppm (triplet,
7.55 ppm (triplet, 1H); 7.72 ppm (doublet, 1H); 7.90 ppm (doublet, 1H); 8.02 ppm (doublet, 1H); 8.52 ppm (doublet, 1H); 13.68 ppm (multiplet, 1H) ).

５−ブロモ−２−（１Ｈ−インダゾール−３−イル）−３Ｈ−ベンゾイミダゾールは、５,６−ジメチル−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール
（実施例１５）の製造について記載した手順に従って製造できる：
ジメチルホルムアミド１５ｍｌ中の１Ｈ−インダゾール−３−カルボキシアルデヒド６４３ｍｇ、４−ブロモ−１,２−フェニレンジアミン８１６ｍｇ、およびメタ亜硫酸水素ナトリウム８３６.５ｍｇを出発物質として、ＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノール溶液で抽出）により精製し、続けて圧力下のシリカ上クロマトグラフィーにより精製して、５−ブロモ−２−（１Ｈ−インダゾール−３−イル）−３Ｈ−ベンゾイミダゾール９３９ｍｇを、赤レンガ色粉末の形態で得た。 Example 18
5-Bromo-2- (1H-indazol-3-yl) -3H-benzimidazole

5-Bromo-2- (1H-indazol-3-yl) -3H-benzimidazole was obtained from 5,6-dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole (Example 15). Can be produced according to the procedure described for production:
Starting from 643 mg of 1H-indazole-3-carboxaldehyde, 816 mg of 4-bromo-1,2-phenylenediamine and 836.5 mg of sodium metabisulfite in 15 ml of dimethylformamide, SPE (SCX phase, washed with methanol, 2N By extraction with ammoniacal methanol solution) followed by chromatography on silica under pressure to obtain 939 mg of 5-bromo-2- (1H-indazol-3-yl) -3H-benzimidazole as red brick Obtained in the form of a powder.

２−（５−エトキシ−２Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール−４−カルボン酸は、水素、およびパラジウムのような触媒の存在下で、ベンジル基の脱保護により、２−（２−ベンジル−５−エトキシ−２Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール−４−カルボン酸から得ることができる。
２−（２−ベンジル−５−エトキシ−２Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール−４−カルボン酸は、５,６−ジメチル−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール（実施例１５）の製造について記載した手順に従って製造できる：
ニトロベンゼン１ｍｌ中の２−ベンジル−５−エトキシ−２Ｈ−ピラゾール−３−カルボキシアルデヒド２１.６ｍｇ、および３,４−ジアミノ安息香酸ヒドロクロリド１７.７ｍｇを出発物質として、ＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノール溶液で抽出）により精製して、２−（２−ベンジル−５−エトキシ−２Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール−４−カルボン酸５０.９ｍｇを、黄色ラッカーの形態で得た。 Example 19
2- (5-Ethoxy-2H-pyrazol-3-yl) -1H-benzimidazole-4-carboxylic acid

2- (5-Ethoxy-2H-pyrazol-3-yl) -1H-benzimidazole-4-carboxylic acid is obtained by deprotection of the benzyl group in the presence of hydrogen and a catalyst such as palladium. It can be obtained from 2-benzyl-5-ethoxy-2H-pyrazol-3-yl) -1H-benzimidazole-4-carboxylic acid.
2- (2-Benzyl-5-ethoxy-2H-pyrazol-3-yl) -1H-benzimidazole-4-carboxylic acid is 5,6-dimethyl-2- (1H-indazol-3-yl) -1H Can be prepared according to the procedure described for the preparation of benzimidazole (Example 15):
Starting with 21.6 mg of 2-benzyl-5-ethoxy-2H-pyrazole-3-carboxaldehyde and 17.7 mg of 3,4-diaminobenzoic acid hydrochloride in 1 ml of nitrobenzene, SPE (SCX phase, washed with methanol) Extracted with 2N ammoniacal methanol solution) to give 50.9 mg of 2- (2-benzyl-5-ethoxy-2H-pyrazol-3-yl) -1H-benzimidazole-4-carboxylic acid, yellow lacquer Obtained in the form of

2-Benzyl-5-ethoxy-2H-pyrazole-3-carboxaldehyde can be prepared by the following method:
4Å molecular sieves were added to a solution of 45.7 mg (2-benzyl-5-ethoxy-2H-pyrazol-3-yl) methanol in 0.5 ml dichloromethane followed by 43.1 mg pyridinium chromium chloride. After 20 hours at about 20 ° C., the reaction mixture was filtered through celite. The insoluble material formed was rinsed with ethyl acetate and then with dichloromethane. The filtrate was washed with water. After standing and separating the phases, the aqueous phase was re-extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and then concentrated under reduced pressure. In this way 21.6 mg of 2-benzyl-5-ethoxy-2H-pyrazole-3-carboxaldehyde was obtained in the form of a brown lacquer, the properties of which were as follows:
1H NMR, DMSO d6, 400 MHz: 1.35 ppm (triplet, 3H); 4.25 ppm (quartet, 2H); 5.30 ppm (singlet, 2H); 6.30 ppm (singlet, 1H); 7.25-7.40 ppm (multiplet, 5H ); 9.72 ppm (singlet, 1H).

(2-Benzyl-5-ethoxy-2H-pyrazol-3-yl) methanol can be prepared by the following method:
11.1 mg of lithium aluminum hydride was added to a solution of 76 mg of methyl 2-benzyl-5-ethoxy-2H-pyrazole-3-carboxylate in 0.75 ml of tetrahydrofuran and cooled to about 0 ° C. with an ice bath. After 3 hours at about 0 ° C., 22.2 mg of lithium aluminum hydride was added and the reaction solvent was warmed to about 20 ° C. After 30 minutes at about 20 ° C., 10 ml of ice cold water was added and the reaction mixture was then filtered through celite. After standing and separating the phases, the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over magnesium sulfate and concentrated under reduced pressure. In this way, 45.7 mg of (2-benzyl-5-ethoxy-2H-pyrazol-3-yl) methanol was obtained in the form of a brown lacquer, the properties of which were as follows:
1H NMR, DMSO d6, 400 MHz: 1.35 ppm (triplet, 3H); 4.15 ppm (quartet, 2H); 4.30 ppm (doublet, 2H); 5.00 ppm (triplet, 1H); 5.08 ppm (singlet, 2H); 5.70 ppm (Singlet, 1H); 7.20-7.40 ppm (Multiplet, 5H).

Methyl 2-benzyl-5-ethoxy-2H-pyrazole-3-carboxylate can be prepared by the following method:
5 mg sodium iodide, 36 μl bromoethane and 70 mg potassium carbonate were added at about 20 ° C. to a solution of 100 mg methyl 2-benzyl-5-hydroxy-2H-pyrazole-3-carboxylate in 1 ml acetone. The reaction mixture was refluxed for 9 hours, cooled to about 20 ° C. and filtered. The filtrate was concentrated under reduced pressure. In this way, 76 mg of methyl 2-benzyl-5-ethoxy-2H-pyrazole-3-carboxylate were obtained in the form of a solid, the properties of which were as follows:
1H NMR, DMSO d6, 400 MHz: 1.35 ppm (triplet, 3H); 3.50 ppm (singlet,
3H); 4.22 ppm (quartet, 2H); 5.22 ppm (singlet, 2H); 6.28 ppm (singlet, 1H); 7.20-7.40 ppm (multiplet, 5H).

Methyl 2-benzyl-5-hydroxy-2H-pyrazole-3-carboxylate can be prepared by the following method:
1.72 ml of dimethyl acetylenedicarboxylate was added at about 20 ° C. to a solution of 2.73 g of benzylhydrazine dihydrochloride in 45 ml of glacial acetic acid. The reaction mixture was refluxed for 3 hours, cooled to about 20 ° C. and then concentrated under reduced pressure. The insoluble material formed was filtered off and 252 mg of methyl 2-benzyl-5-hydroxy-2H-pyrazole-3-carboxylate was recovered in the form of a white powder, the characteristics of which were as follows:
1H NMR, DMSO d6, 400 MHz: 3.76 ppm (singlet, 3H); 5.19 ppm (singlet,
2H); 5.85 ppm (singlet, 1H); 7.25-7.45 ppm (multiplet, 5H); 11.69 ppm
(Multiplet, 1H).
The filtrate is purified by flash chromatography on 400 g of 20-45 μm silica (applied in a 25/75 ethyl acetate / cyclohexane mixture; elution: 25/75, and then 40/60 ethyl acetate / cyclohexane) to give further methyl 2 A batch of -benzyl-5-hydroxy-2H-pyrazole-3-carboxylate was obtained in the form of a white powder.

５,６−ジメチル−２−（５−メチル−２Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾールは、５,６−ジメチル−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール（実施例１５）の製造について記載した手順に従って製造できる：
エタノール０.５ｍｌおよびジメチルホルムアミド１.５ｍｌ中の、５−メチル−２Ｈ−ピラゾール−３−カルボキシアルデヒド５３.３ｍｇ、４,５−ジメチル−１,２−フェニレンジアミン６５.９ｍｇ、およびメタ亜硫酸水素ナトリウム９２ｍｇを出発物質として、ＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノール溶液で抽出）により精製し、次いで圧力下のシリカ上クロマトグラフィーで精製して、５,６−ジメチル−２−（５−メチル−２Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾール２０.８ｍｇを白色粉末の形態で得た。 Example 20
5,6-Dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -1H-benzimidazole

5,6-Dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -1H-benzimidazole is 5,6-dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole. Can be prepared according to the procedure described for the preparation of Example 15:
5-methyl-2H-pyrazole-3-carboxaldehyde 53.3 mg, 4,5-dimethyl-1,2-phenylenediamine 65.9 mg, and sodium metabisulfite in 0.5 ml ethanol and 1.5 ml dimethylformamide 92 mg starting material was purified by SPE (SCX phase, washed with methanol, extracted with 2N ammoniacal methanol solution) and then purified by chromatography on silica under pressure to give 5,6-dimethyl-2- (5 20.8 mg of -methyl-2H-pyrazol-3-yl) -1H-benzimidazole were obtained in the form of a white powder.

  5-Methyl-2H-pyrazole-3-carboxaldehyde is prepared according to the procedure described for the preparation of 1H-indazole-3-carboxaldehyde starting from methyl 3-indazolecarboxylate as the starting material ethyl 5-methyl-2H- It can be produced from pyrazole-3-carboxylate.

５,６−ジメチル−２−（５−チオフェン−２−イル−２Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾールは、５,６−ジメチル−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール（実施例１５）の製造について記載した手順に従って製造できる：
エタノール０.２ｍｌおよびジメチルホルムアミド０.６ｍｌ中の、５−チオフェン−２−イル−２Ｈ−ピラゾール−３−カルボキシアルデヒド１６.２ｍｇ、４,５−ジメチル−１,２−フェニレンジアミン１２.４ｍｇ、およびメタ亜硫酸水素ナトリウム１７.３ｍｇを出発物質として、ＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノール溶液で抽出）により精製し、次いで圧力下のシリカ上クロマトグラフィーにより精製し、そしてＬＣ／ＭＳにより精製して、５,６−ジメチル−２−（５−チオフェン−２−イル
−２Ｈ−ピラゾール−３−イル）−１Ｈ−ベンゾイミダゾールを白色粉末の形態で得た。
５−チオフェン−２−イル−２Ｈ−ピラゾール−３−カルボキシアルデヒドは、１Ｈ−インダゾール−３−カルボキシアルデヒドについて記載した手順に従って、メチル３−インダゾールカルボキシレートを出発物質として、市販のエチル５−チオフェン−２−イル−２Ｈ−ピラゾール−３−カルボキシレートから製造できる。 Example 21
5,6-Dimethyl-2- (5-thiophen-2-yl-2H-pyrazol-3-yl) -1H-benzimidazole

5,6-Dimethyl-2- (5-thiophen-2-yl-2H-pyrazol-3-yl) -1H-benzimidazole is 5,6-dimethyl-2- (1H-indazol-3-yl)- It can be prepared according to the procedure described for the preparation of 1H-benzimidazole (Example 15):
16.2 mg of 5-thiophen-2-yl-2H-pyrazole-3-carboxaldehyde in 0.2 ml of ethanol and 0.6 ml of dimethylformamide, and 12.4 mg of 4,5-dimethyl-1,2-phenylenediamine, and Purified by SPE (SCX phase, washed with methanol, extracted with 2N ammoniacal methanol solution), then purified by chromatography on silica under pressure, and by LC / MS starting with 17.3 mg sodium metabisulfite Purification gave 5,6-dimethyl-2- (5-thiophen-2-yl-2H-pyrazol-3-yl) -1H-benzimidazole in the form of a white powder.
5-thiophen-2-yl-2H-pyrazole-3-carboxaldehyde is prepared according to the procedure described for 1H-indazole-3-carboxaldehyde starting from methyl 3-indazolecarboxylate as the starting material ethyl 5-thiophene- It can be prepared from 2-yl-2H-pyrazole-3-carboxylate.

２−（４−ブロモ−２Ｈ−ピラゾール−３−イル）−５,６−ジメチル−１Ｈ−ベンゾイミダゾールは、５,６−ジメチル−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール（実施例１５）の製造について記載した手順に従って製造できる：
エタノール１ｍｌおよびジメチルホルムアミド２ｍｌ中の、市販の４−ブロモ−２Ｈ−ピラゾール−３カルボキシアルデヒド１００ｍｇ、４,５−ジメチル−１,２−フェニレンジアミン７７.８ｍｇ、およびメタ亜硫酸水素ナトリウム１０８.６ｍｇを出発物質として、ＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノール溶液で抽出）により精製し、次いで圧力下のシリカ上クロマトグラフィーにより精製して、２−（４−ブロモ−２Ｈ−ピラゾール−３−イル）−５,６−ジメチル−１Ｈ−ベンゾイミダゾール１４３.２ｍｇを、黄色泡状物の形態で得た。 [Example 22]
2- (4-Bromo-2H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole

2- (4-Bromo-2H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole is 5,6-dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole Can be prepared according to the procedure described for the preparation of Example 15:
Starting with 100 mg of commercially available 4-bromo-2H-pyrazole-3 carboxaldehyde, 77.8 mg of 4,5-dimethyl-1,2-phenylenediamine and 108.6 mg of sodium metabisulfite in 1 ml of ethanol and 2 ml of dimethylformamide The material was purified by SPE (SCX phase, washed with methanol, extracted with 2N ammoniacal methanol solution) and then purified by chromatography on silica under pressure to give 2- (4-bromo-2H-pyrazole-3- Yl) -5,6-dimethyl-1H-benzimidazole 143.2 mg was obtained in the form of a yellow foam.

２−（５−エチル−２Ｈ−ピラゾール−３−イル）−５,６−ジメチル−１Ｈ−ベンゾイミダゾールは、５,６−ジメチル−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール（実施例１５）の製造について記載した手順に従って製造できる：
エタノール１ｍｌおよびジメチルホルムアミド３ｍｌ中の、５−エチル−２Ｈ−ピラゾール−３−カルボキシアルデヒド１００ｍｇ、４,５−ジメチル−１,２−フェニレンジアミン１１０ｍｇ、およびメタ亜硫酸水素ナトリウム１５３ｍｇを出発物質として、ＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノール溶液で抽出）により精製し、次いで逆相ＨＰＬＣ（５ｍｍ Ｃ１８相、寸法１００x２５ｍｍ、流速２０ｍｌ／分、溶出勾配 アセトニトリル／０.０７％ＴＦＡ−水／０.０７％ＴＦＡ、５−９５〜９５−５（v／v））により精製し、そしてＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノール溶液で抽出）により脱塩して、２−（５−エチル−２Ｈ−ピラゾール−３−イル）−５,６−ジメチル−１Ｈ−ベンゾイミダゾール８２ｍｇを、ベージュ色粉末の形態で得、その特性は以下のとおりであった：
1H NMR, DMSO d6, 300 MHz: 1.26 (t, J = 7 Hz: 3H); 2.31 (s: 6H); 2.70 (ブロードq, J = 7 Hz: 2H); 6.60 (ブロード s: 1H); 7.22 (マルチプレット: 1H); 7.36 (マルチプレット: 1H); 12.37 (マルチプレット: 1H); 12.92 (マルチプレット: 1H). Example 23
2- (5-Ethyl-2H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole

2- (5-Ethyl-2H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole is 5,6-dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole Can be prepared according to the procedure described for the preparation of Example 15:
Starting with 100 mg of 5-ethyl-2H-pyrazole-3-carboxaldehyde, 110 mg of 4,5-dimethyl-1,2-phenylenediamine and 153 mg of sodium metabisulfite in 1 ml of ethanol and 3 ml of dimethylformamide, SPE ( Purification by SCX phase, washing with methanol and extraction with 2N ammoniacal methanol solution, followed by reverse phase HPLC (5 mm C18 phase, dimensions 100 × 25 mm, flow rate 20 ml / min, elution gradient acetonitrile / 0.07% TFA-water / 0.00. 07% TFA, 5-95 to 95-5 (v / v)) and desalted with SPE (SCX phase, washed with methanol, extracted with 2N ammoniacal methanol solution) to give 2- (5- Ethyl-2H-pyrazol-3-yl) -5,6-dimethyl-1H-be 82 mg of nzoimidazole was obtained in the form of a beige powder, the characteristics of which were as follows:
1H NMR, DMSO d6, 300 MHz: 1.26 (t, J = 7 Hz: 3H); 2.31 (s: 6H); 2.70 (broad q, J = 7 Hz: 2H); 6.60 (broad s: 1H); 7.22 (Multiplet: 1H); 7.36 (Multiplet: 1H); 12.37 (Multiplet: 1H); 12.92 (Multiplet: 1H).

5-Ethyl-2H-pyrazole-3-carboxaldehyde is prepared according to the procedure described for the preparation of 1H-indazole-3-carboxaldehyde starting from methyl 3-indazolecarboxylate. It can be produced from 3-carboxylate.
Ethyl 5-ethyl-2H-pyrazole-3-carboxylate can be prepared according to the general procedure in the following reference: Kunio Seki et al., Chem. Pharm. Bull., 32 (4), 1568-1577 (1984).

２−（５−エチル−２Ｈ−ピラゾール−３−イル）−４,５−エチレンジオキシ−１Ｈ−ベンゾイミダゾールは、５,６−ジメチル−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール（実施例１５）の製造について記載した手順に従って製造できる：
エタノール１ｍｌおよびジメチルホルムアミド３ｍｌ中の、５−エチル−２Ｈ−ピラゾール−３−カルボキシアルデヒド１００ｍｇ、３,４−エチレンジオキシ−１,２−フェニレンジアミン１３４ｍｇ、およびメタ亜硫酸水素ナトリウム１５３ｍｇを出発物質として、ＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノール溶液で抽出）により精製し、次いで逆相ＨＰＬＣ（５ｍｍ Ｃ１８相、寸法１００x２５ｍｍ、流速 ２０ｍｌ／分、溶出勾配 アセトニトリル／０.０７％ＴＦＡ−水／０.０７％ＴＦＡ、５−９５〜９５−５(v／v)）により精製し、そしてＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノール溶液で抽出）により脱塩して、２−（５−エチル−２Ｈ−ピラゾール−３−イル）−４,５−エチレンジオキシ−１Ｈ−ベンゾイミダゾール６０ｍｇを、褐色ラッカーの形態で得、その特性は以下のとおりであった：
1H NMR, DMSO d6, 300 MHz: 1.27 (t, J = 7 Hz: 3H); 2.70 (ブロード q, J = 7 Hz: 2H); 4.20 〜 4.45 (mt: 4H); 6.61 (ブロード s: 1H); 6.72 (d, J = 8 Hz: 1H); 6.88 (ブロード d, J = 8 Hz: 1H); 12.50 (マルチプレット: 1H); 12.94 (マルチプレット: 1H). Example 24
2- (5-Ethyl-2H-pyrazol-3-yl) -4,5-ethylenedioxy-1H-benzimidazole

2- (5-Ethyl-2H-pyrazol-3-yl) -4,5-ethylenedioxy-1H-benzimidazole is 5,6-dimethyl-2- (1H-indazol-3-yl) -1H- Can be prepared according to the procedure described for the preparation of benzimidazole (Example 15):
Starting from 100 mg of 5-ethyl-2H-pyrazole-3-carboxaldehyde, 134 mg of 3,4-ethylenedioxy-1,2-phenylenediamine and 153 mg of sodium metabisulfite in 1 ml of ethanol and 3 ml of dimethylformamide, Purified by SPE (SCX phase, washed with methanol, extracted with 2N ammoniacal methanol solution), then reverse phase HPLC (5 mm C18 phase, dimensions 100 × 25 mm, flow rate 20 ml / min, elution gradient acetonitrile / 0.07% TFA-water / 0.07% TFA, 5-95 to 95-5 (v / v)) and desalted with SPE (SCX phase, washed with methanol, extracted with 2N ammoniacal methanol solution) to give 2- ( 5-ethyl-2H-pyrazol-3-yl) -4,5-ethylenedio 60 mg of xy-1H-benzimidazole was obtained in the form of a brown lacquer, the properties of which were as follows:
1H NMR, DMSO d6, 300 MHz: 1.27 (t, J = 7 Hz: 3H); 2.70 (broad q, J = 7 Hz: 2H); 4.20 to 4.45 (mt: 4H); 6.61 (broad s: 1H) 6.72 (d, J = 8 Hz: 1H); 6.88 (broad d, J = 8 Hz: 1H); 12.50 (multiplet: 1H); 12.94 (multiplet: 1H).

２−（５−エチル−２Ｈ−ピラゾール−３−イル）−５−メトキシ−１Ｈ−ベンゾイミダゾールは、５,６−ジメチル−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール（実施例１５）の製造について記載した手順に従って製造できる：
エタノール１ｍｌおよびジメチルホルムアミド３ｍｌ中の、５−エチル−２Ｈ−ピラゾール−３−カルボキシアルデヒド１００ｍｇ、４−メトキシ−１,２−フェニレンジアミン１３８ｍｇ、およびメタ亜硫酸水素ナトリウム１５３ｍｇを出発物質として、ＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノール溶液で抽出）により精製し、次いで逆相ＨＰＬＣ（５ｍｍ Ｃ１８相、寸法 １００x２５ｍｍ、流速 ２０ｍｌ／分、溶出勾配 アセトニトリル／０.０７％ＴＦＡ−水／０.０７％ＴＦＡ、５−９５〜９５−５(v／v)）により精製し、そしてＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノール溶液で抽出）により脱塩して、２−（５−エチル−２Ｈ−ピラゾール−３−イル）−５−メトキシ−１Ｈ−ベンゾイミダゾール６１ｍｇを、褐色ラッカーの形態で得、その特性は以下のとおりであった：
1H NMR, DMSO d6 (CD3COOD数滴を添加), 300 MHz: 1.26 (t, J = 7 Hz: 3H); 2.70 (q,
J = 7 Hz: 2H); 3.79 (s: 3H); 6.61 (s: 1H); 6.81 (dd, J = 8.5 および 2.5 Hz: 1H); 7.03 (ブロード s: 1H); 7.42 (d, J = 8.5 Hz: 1H). Example 25
2- (5-Ethyl-2H-pyrazol-3-yl) -5-methoxy-1H-benzimidazole

2- (5-Ethyl-2H-pyrazol-3-yl) -5-methoxy-1H-benzimidazole is 5,6-dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole Can be prepared according to the procedure described for the preparation of Example 15):
Starting with 100 mg 5-ethyl-2H-pyrazole-3-carboxaldehyde, 138 mg 4-methoxy-1,2-phenylenediamine and 153 mg sodium metabisulfite in 1 ml ethanol and 3 ml dimethylformamide as starting materials, SPE (SCX phase , Washed with methanol, extracted with 2N ammoniacal methanol solution), then reverse phase HPLC (5 mm C18 phase, dimensions 100 × 25 mm, flow rate 20 ml / min, elution gradient acetonitrile / 0.07% TFA-water / 0.07% TFA, 5-95 to 95-5 (v / v)) and desalted with SPE (SCX phase, washed with methanol, extracted with 2N ammoniacal methanol solution) to give 2- (5-ethyl- 2H-pyrazol-3-yl) -5-methoxy-1H-benzoy The imidazole 61 mg, obtained in the form of a brown lacquer, the characteristics were as follows:
1H NMR, DMSO d6 (with few drops of CD3COOD), 300 MHz: 1.26 (t, J = 7 Hz: 3H); 2.70 (q,
J = 7 Hz: 2H); 3.79 (s: 3H); 6.61 (s: 1H); 6.81 (dd, J = 8.5 and 2.5 Hz: 1H); 7.03 (broad s: 1H); 7.42 (d, J = (8.5 Hz: 1H).

２−（５−エチル−２Ｈ−ピラゾール−３−イル）−４−ヒドロキシ−１Ｈ−ベンゾイミダゾールは、５,６−ジメチル−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール（実施例１５）の製造について記載した手順に従って製造できる：
エタノール１ｍｌおよびジメチルホルムアミド３ｍｌ中の、５−エチル−２Ｈ−ピラゾール−３−カルボキシアルデヒド１００ｍｇ、２,３−ジアミノフェノール１００ｍｇ、およびメタ亜硫酸水素ナトリウム１５３ｍｇを出発物質として、ＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノール溶液で抽出）により精製し、次いで逆相ＨＰＬＣ（５ｍｍ Ｃ１８相、寸法 １００x２５ｍｍ、流速 ２０ｍｌ／分、溶出勾配 アセトニトリル／０.０７％ＴＦＡ−水／０.０７％ＴＦＡ、５−９５〜９５−５(v／v)）により精製し、そしてＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノール溶液で抽出）により脱塩して、２−（５−エチル−２Ｈ−ピラゾール−３−イル）−４−ヒドロキシ−１Ｈ−ベンゾイミダゾール１６ｍｇを、褐色ラッカーの形態で得、その特性は以下のとおりであった：
1H NMR, DMSO d6 (CD3COOD数滴を添加), 300 MHz: 1.26 (t, J = 7 Hz: 3H); 2.70 (q,
J = 7 Hz: 2H); 6.55 (t, J = 4.5 Hz: 1H); 6.66 (s: 1H); 6.96 (ブロード d, J = 4.5 Hz: 2H). Example 26
2- (5-Ethyl-2H-pyrazol-3-yl) -4-hydroxy-1H-benzimidazole

2- (5-Ethyl-2H-pyrazol-3-yl) -4-hydroxy-1H-benzimidazole is 5,6-dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole Can be prepared according to the procedure described for the preparation of Example 15):
SPE (SCX phase, washed with methanol) starting from 100 mg 5-ethyl-2H-pyrazole-3-carboxaldehyde, 100 mg 2,3-diaminophenol and 153 mg sodium metabisulfite in 1 ml ethanol and 3 ml dimethylformamide Purified by 2N ammoniacal methanol solution) and then reverse phase HPLC (5 mm C18 phase, dimensions 100 × 25 mm, flow rate 20 ml / min, elution gradient acetonitrile / 0.07% TFA-water / 0.07% TFA, 5- 95-95-5 (v / v)) and desalted with SPE (SCX phase, washed with methanol, extracted with 2N ammoniacal methanol solution) to give 2- (5-ethyl-2H-pyrazole- 3-yl) -4-hydroxy-1H-benzimidazole 1 The mg, obtained in the form of a brown lacquer, the characteristics were as follows:
1H NMR, DMSO d6 (with few drops of CD3COOD), 300 MHz: 1.26 (t, J = 7 Hz: 3H); 2.70 (q,
J = 7 Hz: 2H); 6.55 (t, J = 4.5 Hz: 1H); 6.66 (s: 1H); 6.96 (broad d, J = 4.5 Hz: 2H).

２−（５−エチル−２Ｈ−ピラゾール−３−イル）−５−ブロモ−１Ｈ−ベンゾイミダゾールは、５,６−ジメチル−２−（１Ｈ−インダゾール−３−イル）−１Ｈ−ベンゾイミダゾール（実施例１５）の製造について記載した手順に従って製造できる：
エタノール１ｍｌおよびジメチルホルムアミド２ｍｌ中の、５−エチル−２Ｈ−ピラゾール−３−カルボキシアルデヒド２０ｍｇ、４−ブロモ−１,２−フェニレンジアミン３０ｍｇ、およびメタ亜硫酸水素ナトリウム３０ｍｇを出発物質として、ＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノール溶液で抽出）により精製し、次いで逆相ＨＰＬＣ（５ｍｍ Ｃ１８相、寸法 １００x２５ｍｍ、流速 ２０ｍｌ／分、溶出勾配 アセトニトリル／０.０７％ＴＦＡ−水／０.０７％ＴＦＡ、５−９５〜９５−５(v／v)）により精製し、そしてＳＰＥ（ＳＣＸ相、メタノールで洗浄、２Ｎアンモニア性メタノール溶液で抽出）により脱塩して、２−（５−エチル−２Ｈ−ピラゾール−３−イル）−５−ブロモ−１Ｈ−ベンゾイミダゾール２１ｍｇを、黄色粉末の形態で得、その特性は以下のとおりであった：
1H NMR, DMSO d6, 300 MHz: 1.28 (t, J = 7 Hz: 3H); 2.71 (q, J = 7 Hz: 2H); 6.67
(s: 1H); 7.30 (dd, J = 8.5 および 2.5 Hz: 1H); 7.49 (mt: 1H); 7.712 (ブロード s: 1H); 12.5〜13.5 (ブロード マルチプレット: 2H). Example 27
2- (5-Ethyl-2H-pyrazol-3-yl) -5-bromo-1H-benzimidazole

2- (5-Ethyl-2H-pyrazol-3-yl) -5-bromo-1H-benzimidazole is 5,6-dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole Can be prepared according to the procedure described for the preparation of Example 15):
Starting from 20 mg 5-ethyl-2H-pyrazole-3-carboxaldehyde, 30 mg 4-bromo-1,2-phenylenediamine and 30 mg sodium metabisulfite in 1 ml ethanol and 2 ml dimethylformamide as starting materials, SPE (SCX phase , Washed with methanol, extracted with 2N ammoniacal methanol solution), then reverse phase HPLC (5 mm C18 phase, dimensions 100 × 25 mm, flow rate 20 ml / min, elution gradient acetonitrile / 0.07% TFA-water / 0.07% TFA, 5-95 to 95-5 (v / v)) and desalted with SPE (SCX phase, washed with methanol, extracted with 2N ammoniacal methanol solution) to give 2- (5-ethyl- 2H-pyrazol-3-yl) -5-bromo-1H-benzimidazole The 1 mg, obtained in the form of a yellow powder, the characteristics were as follows:
1H NMR, DMSO d6, 300 MHz: 1.28 (t, J = 7 Hz: 3H); 2.71 (q, J = 7 Hz: 2H); 6.67
(s: 1H); 7.30 (dd, J = 8.5 and 2.5 Hz: 1H); 7.49 (mt: 1H); 7.712 (broad s: 1H); 12.5 to 13.5 (broad multiplet: 2H).

以下の図１の表に示される本出願の実施例９７〜１４５の生成物は、上記で示したスキームに従って、特に、以下に示す手順に従って製造することができる。 The product of formula (I) of the present application can also be prepared according to the following steps:

The products of Examples 97-145 of the present application shown in the table of FIG. 1 below can be prepared according to the scheme shown above, in particular according to the procedure shown below.

Example 97
3- (6-Phenyl-1H-benzimidazol-2-yl) -2H-indazole Step 1: Synthesis of 3- (6-Bromo-1H-benzimidazol-2-yl) -2H-indazole 1-Hydroxybenzotriazole 4.25 g and 4.3 g of calcium sulfate were added to a solution of 4.6 g of indazole-3-carboxylic acid in 50 ml of dimethylformamide at ambient temperature. The reaction mixture was cooled to about 0 ° C. and then 4.9 ml N, N-diisopropylcarbodiimide was added slowly. After stirring for 2 hours at ambient temperature, 5.9 g of 4-bromo-o-phenylenediamine was added. After stirring for 60 hours at ambient temperature, the reaction mixture was concentrated to dryness under reduced pressure. The resulting brown oil was taken up in 50 ml of water and extracted three times with 50 ml of ethyl acetate. The organic phases were combined, dried over magnesium sulfate and then concentrated to dryness under reduced pressure. This gave 18 g of a brown oil which was taken up in 100 ml of a 20% hydrochloric acid solution in ethanol. The mixture was refluxed for 4 hours, then concentrated to dryness, the resulting brown oil was taken up in 20 ml of water and aqueous ammonia was added until the pH of the mixture was about 8-9. The aqueous phase was then extracted three times with 30 ml of ethyl acetate and the organic phases were combined, dried over magnesium sulfate and concentrated to dryness under reduced pressure. Purification by chromatography on silica under pressure (eluent water / acetonitrile) gave 5 g of 3- (6-bromo-1H-benzimidazol-2-yl) -2H-indazole.
IR spectrum (KBr): characteristic bands at 1621, 1570, 1441, 1344, 1324, 1273, 1239, 1135, 1042, 914, 804, 774 and 746cm- ¹

Step 2: Synthesis of 1- [2- (1-acetyl-1H-indazol-3-yl) -5-benzimidazol-1-yl] ethanone 3- (6-Bromo-1H-benzimidazol-2-yl) 2 g of -2H-indazole was added to a solution of 40 ml acetic anhydride and 40 ml pyridine. The mixture was refluxed for 4 hours and then concentrated to dryness after returning to ambient temperature. The resulting brown solid was taken up in 50 ml of ethyl acetate and washed with 50 ml of saturated sodium bicarbonate solution until the pH was 7-8. The organic phase was dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The resulting light brown solid was triturated in 20 ml of ethyl acetate and filtered on a sintered glass funnel. Thus, the compound 1- [2- (1-acetyl-1H-indazole-3)
1.5 g of -yl) -5-bromobenzimidazol-1-yl] ethanone were obtained. The filtrate obtained above was chromatographed on silica under pressure (eluent cyclohexane / ethyl acetate) to give a second crop, 1.3 g of the same compound.

Compound properties:
¹ H NMR spectrum (300 MHz, (CD ₃ ) ₂ SO d6, δ (ppm)).
A mixture of two regioisomers was observed at a ratio of 50/50.
2.61 and 2.62 (2 s, 3H total); 2.80 (s, 3H); 7.62 (broad t, J = 7.5 Hz, 1H); 7.68 and 7.71 (2 dd, J = 9 and 2 Hz, 1H total); 7.80 (ddd, J = 8.5, 7.5 and 0.5 Hz, 1H); 7.91 and 8.01 (2 d, J = 9 Hz, 1H); 8.18 and 8.20 (2 d, J = 2 Hz, 1H total); 8.27 and 8.30 ( 2 d, J = 7.5 Hz, 1H total); 8.46 (d, J = 8.5 Hz, 1H)
IR spectrum (KBr): characteristic bands at 1727, 1610, 1450, 1405, 1374, 1326, 1290, 1198, 1176, 964 and 760cm ^-1

Step 3: Synthesis of 3- (6-phenyl-1H-benzimidazol-2-yl) -2H-indazole Sodium carbonate 40 mg, dihydrogen dichlorobis- (di-tert-butylphosphonite-κP) paradate (2-) ( 1 mg of POPd [0]) and 46 mg of phenylboric acid in 800 μl of anhydrous tetrahydrofuran under an argon atmosphere in 1- [2- (1-acetyl-1H-indazol-3-yl) -5-phenylbenzimidazole-1 -Il] ethanone was added to a solution of 50 mg. The reaction mixture was refluxed for 3 hours and then cooled to ambient temperature. The mixture was then diluted with 3 ml of ethyl acetate and washed twice with 2 ml of water. The organic phase was dried over magnesium sulfate and concentrated to dryness under reduced pressure. 48 mg of a brown solid was obtained, and this solid was dissolved in 500 μl of tetrahydrofuran, and 500 μl of diethylamine was added thereto. The reaction mixture was heated at 60 ° C. for 4 hours and then returned to ambient temperature. The mixture was then concentrated to dryness and the resulting brown solid was purified by LC / MS to give 3- (6-phenyl-1H-benzimidazol-2-yl) -2H-indazole (6) 12. was obtained 5 mg; analytical retention time 3.10, MS311 [M + H] +.

実施例９８〜１４５の生成物の合成は、３−（６−フェニル−１Ｈ−ベンゾイミダゾール−２−イル）−２Ｈ−インダゾール（実施例９７）の合成と同様の方法において、フェニルホウ酸を式ＲＢ(ＯＨ)₂のホウ酸で置き換えることにより行うことができる。 The products of formula (I) of this application, and in particular the products of Examples 98-145, can also be prepared according to the following steps:

The synthesis of the products of Examples 98-145 was carried out in a manner similar to the synthesis of 3- (6-phenyl-1H-benzoimidazol-2-yl) -2H-indazole (Example 97) and phenylboric acid was converted to the formula RB. This can be done by replacing with (OH) ₂ boric acid.

  The products of formula (I) of the present application constituted by Examples 28-96 and 146-180 of the present application are shown in FIG. 1 of the following table, and these products are specifically indicated above. It can be prepared according to the scheme and in particular as indicated above for the product of Example 1.

上記のスキームにおいて、Ｚ３およびＺ４に対応する基は、上記で定義されたＲ２およびＲ３に対応する基から選択され、そしてＺ１および−ＯＺ２に対応する基は、Ｒ１がピラゾール基であるＸ１、Ｘ２またはＸ３に対応する基から選択され、 The product of formula (I) of the present application can also be prepared according to the following steps:

In the above scheme, the groups corresponding to Z3 and Z4 are selected from the groups corresponding to R2 and R3 as defined above, and the groups corresponding to Z1 and -OZ2 are X1, X2 wherein R1 is a pyrazole group Or selected from the group corresponding to X3,

When Z1, Z3 and Z4 represent a hydrogen atom, the product of formula (I) of the present application can be prepared in particular according to the following synthetic scheme:

  The products of formula (I) of the present application constituted by examples 181 to 228 of the present application are shown in the following table: These products can be prepared as shown in the above scheme And in particular the product of Example 181 can be prepared as shown below. The products of Examples 182 to 228 can be prepared similarly to the product of Example 181.

[Example 181]
2- [5- (Benzyloxy) -2H-pyrazol-3-yl] -1H-benzimidazole Step 1: Cyclization is literature: Chem. Pharm. Bull., 31 (4), 1228-1234 (1983); J. Org. Chem., 47 (2), 214-221 (1982).
Step 2: To 1.015 g of the crude ester obtained in Step 1 in 50 ml of MeOH, 5.5 ml of 6N NaOH was added and the mixture was heated to reflux for 2 hours. After evaporation of methanol, the solvent was cooled and concentrated HCl was added until pH = 2. Concentrated to dryness, the solid was treated with 30 ml of MeOH / AcOEt 1/1 three times, and the filtrate was concentrated to give 0.875 g of a light brown solid after drying.
LC / MS: [gradient acetonitrile / water 0.1% HCOOH; Xterra RP18 2.1 × 50 mm] retention time 0.53 min MH + = 129 purity 95%

Stage 3: To 0.7 g of PPA (polyphosphoric acid), 0.701 g of 1,2-phenylenediamine and 0.87 g of the acid obtained in stage 2 above were added. The mixture was heated to 150 ° C. for 1.5 hours. After cooling, concentrated NH4OH was added until pH = 3. The green precipitate was filtered and washed with water and then acetone. The solid was dried overnight at 50 ° C. under vacuum to obtain 2.1 g of a solid containing about 50% of an inorganic acid salt.
MS: EI M + = 200
Step 4: To 80 mg of the product obtained in Step 3 above in 4 ml of NMP, 137 mg of cesium carbonate and 72 mg of benzyl bromide were added. After 2 hours, the mixture was hydrolyzed with saturated KH2PO4 and extracted with AcOEt. After concentration, the mixture was subjected to preparative LC / MS to give 8 mg of pure product.
LC / MS: [gradient acetonitrile / water 0.1% HCOOH; Xterra RP18 2.1 × 50 mm] retention time 3.17 min MH + = 291 purity 97%

  In a manner similar to the preparation of Example 181, step 4 was performed using 15α-bromocarbonyl product and 15 acid chloride in 15 benzyl or allyl bromide, DMF or NMP: Examples 181 to 228 of this application were The desired corresponding product from the table shown below was obtained.

Example 229
Pharmaceutical composition A tablet corresponding to the formula is prepared as follows:
0.2 g of the product of Example 1
1g additive content to the final tablet
(Additive details: lactose, talc, starch, magnesium stearate).
Although Example 1 was listed as an example of a pharmaceutical formulation, this formulation can be made using other products in the examples of this application if desired.

Biological chapter Evaluation of the inhibitory effect of compounds on in vitro test KDR:
I) Biological activity:
The inhibitory effect of the compounds is determined by the flasplate technique (96-well plate, N
EN) in vitro in a phosphorylation test of the substrate by the enzyme KDR.
The cytoplasmic domain of the human KDR enzyme was cloned into the baculovirus expression vector pFastBac in GST fusion form. The protein was expressed in SF21 cells and purified to approximately 60% homogeneity.

  The kinase activity of KDR was measured in 20 mM MOPS, 10 mM MgCl2, 10 mM MnCl2, 1 mM DTT, 2.5 mM EGTA, 10 mM β-glycerophosphate, pH 7.2 in the presence of 10 mM MgCl2, 100 μM Na3VO4, 1 mM NaF. 10 μl of the compound was added at 4 ° C. to 70 μl of kinase buffer containing 100 ng of KDR enzyme. The reaction was started by adding 20 μl of a solution containing 2 μg of substrate (PLγγ fragment SH2-SH3 expressed in the form of GST fusion protein), 2 μC of γ33P [ATP] and 2 μM of cold ATP. After 1 hour incubation at 37 ° C., 1 volume (100 μl) of 200 mM EDTA was added to quench the reaction. The incubation buffer was removed and the wells were washed 3 times with 300 μl PBS. Radioactivity was measured for each well using a Top Count NXT instrument (Packard).

Background noise was determined by measuring radioactivity in quadruplicate wells containing only radioactive ATP and substrate.
Activity controls were measured in quadruplicate wells containing all reagents (γ33P- [ATP], KDR and substrate PLCγ) and no compound.
Inhibition of KDR activity using the compounds of the present invention is shown as the percentage inhibition of control activity measured in the absence of compound.
Compound SU5614 (Calbiochem) (1 μM) was added to each plate as an inhibition control.
Compound IC50 values were calculated by plotting a dose-response curve. IC50 corresponds to the concentration of compound that induces 50% inhibition of kinase activity.

II) Cellular activity on endothelial cells 1) Inhibition of VEGF-dependent proliferation of HDMEC [14C] Anti-KDR activity of the molecule to HDEC (Human Dermal Microvascular Endothelial Cells) in response to VEGF ] -Thymidine incorporation was evaluated.
On day 1, HDMEC (Promocell, course 5-7) was applied at 37 ° C., 5000 cells in 100 μl per well in Cytostar (Amersham) 96-well plates pre-coated with accessory factors (AF, Cascad Biologics). Inoculated with% CO2. On day 2, complete medium (basic medium supplemented with 5% FCS and growth factor mixture) was replaced with minimal medium (basic medium supplemented with 5% FCS) and cells were incubated for 24 hours. On day 3, the medium is fresh medium (supplemented or not supplemented with 100 ng / ml VEGF (R & D System); and with or without a compound of the invention and 0.1 μCi [14C] -thymidine). Changed to 200 μl. Cells were incubated for 4 days at 37 ° C., 5% CO 2. [14C] -thymidine incorporation was then quantified by counting radioactivity. The test was performed in 3 wells. The final DMSO concentration in the test was 0.1%. The% inhibition was calculated according to:
[Cpm (+ VEGF)-cpm (+ VEGF + cpd) / cpm (+ VEGF)-cpm BM5% FCS)] x100

2) Inhibition of TF (tissue factor) production by endothelial cells in response to VEGF Endothelial cells were inoculated at 20000 cells per well in 96-well plates pre-coated with accessory factors. After culturing for 8 hours, the medium was changed and the cells were preincubated with the compound (DMSO final concentration 0.1%) in basal medium for 16 hours. VEGF
(Final concentration 100 ng / ml) was added to induce the synthesis of TF (tissue factor). After 6 hours of incubation, the cells were rinsed and lysed. Tissue factor was then detected using the Imubind ELISA test.

3) Effect of molecules on VEGF-independent growth of HDMEC On day 1 in Cytostar (Amersham) 96-well plates pre-coated with HDMEC (5000 cells per well) with attached factors (AF, Cascad Biologics) Inoculated at 37 ° C. with 5% CO 2. All media was then removed and the cells were incubated in 200 μl complete media containing the molecules of the invention and [14C] -thymidine (0.1 μCi). After incubation for 3 days, [14C] -thymidine incorporation was measured using a Wallac counter. Percent inhibition was calculated as follows: [cpm (CM) -cpm (CM + cpd) / cpm (CM)] × 100.

  The following table shows the results obtained in the above tests for the products shown as examples in this patent application.

For the products shown in the examples of the present application, the pharmacological results obtained in the above test are shown in the table below, the degree of activity of the products is indicated by the + sign according to the range of activities shown in the table Indicated, ie:
+ For activity greater than 3 μM,
++ for an activity of 0.3 to 3 μM,
+++ indicates activity less than 3 μM.

Claims (46)

Formula (I):

[Where:
X represents C—R2, and W, Y and Z may be the same or different and represent CH or CR3;
R1 is aryl or pyrazolyl, triazolyl, imidazolyl, indolyl, indazolyl, thienopyrazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, dihydrofuropyrazolyl, oxodihydropyridazinyl, tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl , Tetrahydropyranopyrazolyl, tetrahydropyridinopyrazolyl, and oxodihydropyridinopyrazolyl groups, all of which optionally represent H, halogen, haloalkyl, OH, R4, NO2, CN , S (O) nR4, OR4, NY1Y2, COR4, -C (= O) NY1Y2, -C (= O) OR4, -C (= O) OH, -N (R6) C (= O) R4,- N (R6) O2R4, -N (R6) C (= O) NY1Y2, -N (R6) C (= O) OR4, -S (O) nOR4, -S (O) nNY1Y2, -OC (= O) NY1Y2, -OS Substituted with one or more groups X1, X2, or X3 selected from (O) nR4, -OC (= O) R4, and thienyl (optionally substituted);
R2 and R3 are:
R2 and R3 may be the same or different, and H, R4, halogen, haloalkyl, OH, NO2, CN, OR4, COR4, S (O) nR4, -C (= O) NY1Y2 , -C (= O) OR4, -C (= O) OH, -NY1Y2, -N (R6) C (= O) R4, -N (R6) SO2R4, -N (R6) C (= O) NY1Y2 , -N (R6) C (= O) OR4, -S (O) nOR4, -S (O) nNY1Y2, -OC (= O) NY1Y2, and -OC (= O) R4,
Or R2 is H, R4, halogen, haloalkyl, OH, NO2, CN, OR4, COR4, S (O) nR4, -C (= O) NY1Y2, -C (= O) OR4, -C (= O) OH, -NY1Y2, -N (R6) C (= O) R4, -N (R6) SO2R4, -N (R6) C (= O) NY1Y2, -N (R6) C (= O) OR4, -S (O) nOR4, -S (O) nNY1Y2, -OC (= O) NY1Y2, and -OC (= O) R4,
And R3 represents alkyl, haloalkyl, halogen and OR6,
Or a ring based on a 5- to 6-membered carbon containing one or more heteroatoms, wherein R2 and R3 together are the same or different and are selected from O, N and S One of which forms
R4 represents alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl, and arylalkyl, all these groups optionally being aryl (optionally substituted) Substituted with one or more groups selected from halogen, alkyl, hydroxyalkyl, OH, OR5, C (= O) NY3Y4, NY3Y4, alk-NY3Y4 and C (= O) OR6 ,
R5 represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, and heterocycloalkylalkyl.
Y1 and Y2 are the following: Y1 and Y2 may be the same or different, H, and optionally substituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl Represents arylalkyl, heteroaryl, and heteroarylalkyl,
Or Y1 and Y2 together with the nitrogen atom to which they are attached form a cyclic amino group,
Y3 and Y4 may be the following: Y3 and Y4 may be the same or different and represent hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, or heteroarylalkyl, or , Y3 and Y4, together with the nitrogen atom to which they are attached, form an optionally substituted cyclic amino group,
A5 represents H or alkyl,
R6 is selected from the definition of R5;
All alkyl (or alk, which represents alkyl), alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups in the above groups are halogen atoms and hydroxyl, cyano, alkyl , Alkoxy, acylamino (NH-COalk), -C (= O) OR6, acyl-C (= O) R6, hydroxyalkyl, carboxyalkyl, S (O) n-alk, S (O) n-NH2, S (O) n-NH (alk), S (O) n-N (alk) 2, CF3, OCF3, NO2, arylalkoxy, aryl, heteroaryl, aryloxy, aryloxyalkyl, -C (= O)- One or more groups selected from the group NY3Y4 and NY3Y4, It is further substituted by engagement,
These later-described groups, including alkyl, aryl, and heteroaryl, are themselves optionally halogen atoms, and alkyl groups, carboxyl groups (which are free, salted, or esterified. ), And one or more groups selected from the acylamino group NH—C (O) R 5,
The phenyl group is optionally further substituted with a dioxole group,
n is an integer from 0 to 2]
A compound of
However, R1 is an indazolyl group, and the following formula (I):

When obtaining a compound of the formula wherein X represents H and R2 or R3 is as defined above, W is understood to necessarily represent H or unsubstituted alkyl;
The compounds of formula (I) may be in all possible racemic, enantiomeric or diastereomeric isomeric forms, and also addition salts with inorganic and organic acids, or addition salts with inorganic bases, A compound of formula (I) above. Formula (Ia):

[Where:
Xa represents C-R2a and Wa, Ya and Za may be the same or different and represent CH or CR3a;
R1a represents aryl or heteroaryl selected from pyrazolyl, triazolyl and indazolyl groups, all these groups optionally being H, halogen, OH, R4a, OR4a, NY1aY2a, S (O) nR4a,- C (= O) NY1aY2a, -C (= O) OR4a, -N (R6a) C (= O) R4a, -N (R6a) SO2R4a, -N (R6a) C (= O) NY1aY2a, -N (R6a ) C (= O) OR4a, -OC (= O) NY1aY2a, -OC (= O) R4a, -OS (O) nR4a, and thienyl (optionally substituted with an alkyl group) 1 Or substituted with more groups X1a, X2a, or X3a,
R2a and R3a are:
R2a and R3a may be the same or different, H, R4a, halogen, OH, OR4a, C (= O) NY1aY2a, -C (= O) OR4a and -C (= O) OH And R3a represents alkyl, halogen and OR6a,
Or R2a represents H, R4a, halogen, OH, OR4a, C (= O) NY1aY2a, -C (= O) OR4a, and -C (= O) OH, and R3a is alkyl, halogen, and Indicate OR6a,
Or R2a and R3a together form an -O-CH2-O- or -O-CH2-CH2-O- ring,
Either
R4a represents alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl, and arylalkyl, all these groups optionally being aryl (optionally substituted) Is substituted with one or more groups selected from halogen, alkyl, hydroxyalkyl, OH, OR5a, C (= O) NY3aY4a, NY3aY4a, alk-NY3aY4a and C (= O) OR6a;
R5a represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocycloalkylalkyl, all of which are optionally substituted;
Y1a and Y2a are the following: Y1a and Y2a may be the same or different, and H, alkyl, alkoxyalkyl, aryloxyalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, cycloalkyl, Aryl and heteroaryl (all these groups are optionally substituted) or a ring in which Y1a and Y2a, together with the nitrogen atom to which they are attached, are optionally substituted Either form a formula amino group,
Y3a and Y4a are as follows: Y3a and Y4a may be the same or different and each represents hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, or heteroarylalkyl, or Either Y3a and Y4a, together with the nitrogen atom to which they are attached, form a cyclic amino group,
A5 represents H or alkyl,
All alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl groups in the above groups are optionally further substituted with halogen atoms and hydroxyl, cyano, alkyl, alkoxy, acylamino (NH -C (O) R6a), -C (= O) OR6a, acyl-C (= O) R6a, hydroxyalkyl, carboxyalkyl, S (O) n-alk, S (O) n-NH2, S (O ) N-NH (alk), S (O) n-N (alk) 2, CF3, OCF3, NO2, arylalkoxy, aryl, heteroaryl, aryloxy, aryloxyalkyl, -C (= O) -NY3aY4a and Substituted with one or more groups selected from the group NY3aY4a Ri,
These later-described groups, including alkyl, aryl, and heteroaryl, are optionally themselves halogen atoms, and alkyl groups, alkoxy groups, carboxyl groups (which are free, salted, or esterified. Substituted with one or more groups selected from the acylamino group NH-C (O) R6a;
The phenyl group is optionally further substituted with a dioxole group,
R6a is selected from the definition of R5a;
n represents an integer of 0 to 2]
A compound of formula (I) according to claim 1 corresponding to
The compounds of formula (Ia) may be in all possible racemic, enantiomeric or diastereomeric isomeric forms, and also addition salts with inorganic and organic acids, or addition salts with inorganic bases, A compound of formula (I) above. A compound of formula (I) according to claim 1 or 2, wherein
X represents C—R2, and W, Y and Z may be the same or different and represent CH or CR3;
R1 is aryl or pyrazolyl, triazolyl, imidazolyl, indolyl, indazolyl, thienopyrazolyl, tetrahydroindazolyl, tetrahydrocyclopentapyrazolyl, dihydrofuropyrazolyl, oxodihydropyridazinyl, tetrahydropyrrolopyrazolyl, oxotetrahydropyrrolopyrazolyl , Tetrahydropyranopyrazolyl, tetrahydropyridinopyrazolyl, and oxodihydropyridinopyrazolyl groups, all of which optionally represent H, halogen, haloalkyl, OH, R4, NO2, CN , S (O) nR4, OR4, NY1Y2, COR4, -C (= O) NY1Y2, -C (= O) OR4, -C (= O) OH, -N (R6) C (= O) R4,- N (R6) O2R4, -N (R6) C (= O) NY1Y2, -N (R6) C (= O) OR4, -S (O) nOR4, -S (O) nNY1Y2, -OC (= O) NY1Y2, -OS Substituted with one or more groups X1, X2, or X3 selected from (O) nR4, -OC (= O) R4, and thienyl (optionally substituted);
R2 and R3 are:
R2 and R3 may be the same or different, H, R4, halogen, haloalkyl, OH, NO2, CN, OR4, COR4, S (O) nR4, -C (= O) NY1Y2, -C (= O) OR4, -C (= O) OH, -NY1Y2, -N (R6) C (= O) R4, -N (R6) SO2R4, -N (R6) C (= O) NY1Y2, -N (R6) C (= O) OR4, -S (O) nOR4, -S (O) nNY1Y2, -OC (= O) NY1Y2, and -OC (= O) R4,
Or R2 is H, R4, halogen, haloalkyl, OH, NO2, CN, OR4, COR4, S (O) nR4, -C (= O) NY1Y2, -C (= O) OR4, -C (= O) OH, -NY1Y2, -N (R6) C (= O) R4, -N (R6) SO2R4, -N (R6) C (= O) NY1Y2, -N (R6) C (= O) OR4, -S (O) nOR4, -S (O) nNY1Y2, -OC (= O) NY1Y2, and -OC (= O) R4,
And R3 represents alkyl, haloalkyl, halogen and OR6,
Or R 2 and R 3 taken together are selected from O, N and S, 5- to 6-membered carbons containing one or more heteroatoms, which may be the same or different Form a ring based on
Either
R4 represents alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl, and arylalkyl, all these groups optionally being aryl, OH, OR5, C (═O) substituted with one or more groups selected from NY3Y4, NY3Y4, and C (═O) OR6;
R5 represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, and heterocycloalkylalkyl;
R6 represents H and C1-C4 alkyl;
n represents an integer of 0 to 2,
Y1 and Y2 may be the following: Y1 and Y2 may be the same or different and may be H, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl (all these groups Is optionally substituted with one or more groups selected from hydroxyl, —C (═O) NY3Y4, —C (═O) OR6, and NY3Y4), or
Or Y1 and Y2 together with the nitrogen atom to which they are attached form a cyclic amino group,
Y3 and Y4 may be the following: Y3 and Y4 may be the same or different and represent hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, or heteroarylalkyl, or Y3 and Y4, together with the nitrogen atom to which they are attached, form a cyclic amino group,
A5 represents H or alkyl,
The compounds of formula (I) may be in all possible racemic, enantiomeric or diastereomeric isomeric forms, and also addition salts with inorganic and organic acids, or addition salts with inorganic bases, Compounds of formula (I) above. Formula (Ia):
[Where:
Xa represents C-R2a, and Wa, Ya and Za may be the same or different and represent CH or CR3a;
R1a represents aryl or heteroaryl selected from pyrazolyl, triazolyl or indazolyl groups, all these groups optionally being H, halogen, OH, R4a, OR4a, NY1aY2a, S (O) nR4,- C (= O) NY1aY2a, -C (= O) OR4a, -N (R6) C (= O) R4a, -N (R6) SO2R4a, -N (R6) C (= O) NY1aY2a, -N (R6 ) C (= O) OR4a, -OC (= O) NY1aY2a, and -OC (= O) R4a, -OS (O) nR4, and thienyl (optionally substituted with an alkyl group); Substituted with one or more groups X1a, X2a or X3a,
R2a and R3a are:
R2a and R3a may be the same or different, and H, R4a, halogen, OH, OR4a, C (= O) NY1Y2, -C (= O) OR4a, -C (= O) OH And R3a represents alkyl, halogen and OR6,
Or R2a represents H, R4a, halogen, OH, OR4a, C (═O) NY1Y2, —C (═O) OR4a, —C (═O) OH, and R3a represents alkyl, halogen, and OR6. Or
Or R2a and R3a together form an -O-CH2-O- or -O-CH2-CH2-O- ring,
Either
R4a represents alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heteroarylalkyl or arylalkyl, all these groups optionally being aryl, OH, OR5a, C (= O) NY3aY4a, NY3aY4a And is substituted with one or more groups selected from C (= O) OR6,
R5a represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocycloalkylalkyl;
R6 represents H and C1-C4 alkyl;
n represents an integer of 0 to 2,
Y1a and Y2a may be the following: Y1a and Y2a may be the same or different, and H, alkyl, cycloalkyl, aryl, and heteroaryl (all these groups are optionally hydroxyl,- C (═O) —NY3aY4a, substituted with one or more groups selected from —C (═O) OR6a and NY3aY4a), or Y1a and Y2a are attached Either taken together with the nitrogen atom to form a cyclic amino group,
Y3a and Y4a are as follows: Y3a and Y4a may be the same or different and each represents hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl, or Y3a and Either Y4a, together with the nitrogen atom to which they are attached, forms a cyclic amino group,
A5 represents H or alkyl.
A compound of formula (I) according to any one of claims 1 to 3, which corresponds to
The compounds of formula (Ia) may be in all possible racemic, enantiomeric or diastereomeric isomeric forms, and also addition salts with inorganic and organic acids, or addition salts with inorganic bases, A compound of formula (I) above. Formula (IA):

[Where:
A represents a saturated heterocyclic group which is either a 5- or 6-membered monocyclic group or a bicyclic group not more than 10-membered, at least two of these ring members being nitrogen atoms And the other ring member is a carbon ring member or a heterocycle member selected from O, N and S, which may be the same or different, the heterocycle A optionally being a group X1, X2 or X3 is substituted with one or more groups XA1, XA2 or XA3 selected from the definitions given in claim 1;
A1, A2, A3 and A4 may be the same or different, and are a hydrogen atom, a halogen atom, and a hydroxyl, alkyl, alkenyl, alkoxy, nitro, cyano, aryl, heteroaryl and aryloxy group A carboxyl group (which is free, salted, esterified with an alkyl group or amidated with the group NA6A7), wherein A6 and A7 are the same May be different or different, hydrogen atoms and optionally substituted alkyl, alkoxyalkyl, phenoxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl groups Selected from or A6 A7, together with the nitrogen atom to which they are attached, optionally form a cyclic group of 5- or 6-membered substituted,
Two consecutive groups out of A1, A2, A3 and A4 together with the benzimidazole group to which they are attached are one or more identical selected from O, N and S It is understood that a ring based on 5- to 6-membered carbon containing heteroatoms that may be different or different may be formed;
A5 represents a hydrogen atom or an alkyl group,
R6b represents hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, phenylalkyl and cycloalkylalkyl;
All alkyl, alkenyl, aryl, heteroaryl, aryloxy, cycloalkyl and heterocycloalkyl groups present in the above groups are optionally halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino. , Phenylamino, phenylalkylamino, acylamino (NH—COR6), —C (═O) OR6b, acyl-C (═O) R6b, hydroxyalkyl, carboxyalkyl, phenoxyalkyl, S (O) n-alk, S (O) n-NH2, S (O) n-NH (alk), S (O) n-N (alk) 2, CF3, OCF3, NO2, CN, phenyl (optionally one or more Substituted with a halogen atom), thienyl, phenoxy, Substituted with one or more groups selected from a phenylalkoxy, -C (= O) -NH2, -C (= O) -NH (alk), and C (= O) -N (alk) 2 groups And
All the above alkyl, alkenyl, alkoxy and alkylthio groups are straight-chain or branched and contain no more than 4 carbon atoms,
All the phenyl groups of the above groups are optionally further substituted with a dioxole group,
n represents an integer of 0 to 2]
Which is a compound of formula (I) according to claim 1,
The compounds of the formula (IA) are all of the possible racemic, enantiomeric or diastereoisomeric forms and also of the formula (IA) with inorganic and organic acids or with inorganic and organic bases A compound of formula (I) above which may be an addition salt of a compound of Formula (IAa):

[Where:
Aa represents a pyrazolyl, triazolyl or indazolyl group, which heterocycle Aa is optionally selected from the definition given in claim 1 for the group X1, X2 or X3, one or more groups XA1, XA2 Or substituted with XA3,
A1a, A2a, A3a and A4a may be the same or different, and are a hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy, nitro, cyano, phenyl and phenoxy group, and a carboxyl group (this is Wherein A6a and A7a are the same or different from each other, are free, salted, esterified with an alkyl group or amidated with the group NA6aA7a) Optionally selected from a hydrogen atom and an alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, thienylalkyl and pyridylalkyl group, or A6a and A7a are the nitrogen to which they are attached. Together with atoms, pyrrolidinyl, pyrazolidinini , Pyrazolinyl, piperidyl, morpholino, or optionally on its second nitrogen atom form a piperazinyl group substituted with an alkyl or phenyl group (optionally substituted themselves),
Two consecutive groups of A1a, A2a, A3a and A4a, together with the benzimidazole group to which they are attached, contain one or two oxygen atoms optionally substituted 5- It is understood that a ring based on a -6-membered carbon can be formed,
A5a represents a hydrogen atom or an alkyl group,
The above phenyl and phenoxy groups are optionally halogen atoms and hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, carboxyl (this is Free, salted or esterified), and substituted with one or more groups selected from dioxol groups,
All the above alkyl, alkoxy and alkylthio groups are linear or branched and contain no more than 6 carbon atoms]
Which is a compound of formula (I) according to claim 1,
The compounds of the formula (IAa) are of the possible racemic, enantiomeric or diastereoisomeric forms and also of the formula (IAa) with inorganic and organic acids or with inorganic and organic bases A compound of formula (I) above which may be an addition salt of a compound of   The compound of formula (I) according to any one of claims 1 to 6, wherein the substituent of the compound of formula (I) is according to any one of claims 1 to 6. Where aryl groups refer to phenyl and naphthyl groups, and heteroaryl groups include furyl, thienyl, benzothienyl, thiantenyl, pyridyl, pyrazolyl, benzimidazolyl, benzofuran, isobenzofuran and dihydrobenzofuran groups. A cycloalkyl group represents a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group; a heterocycloalkyl group represents a hexahydropyran, piperidyl or morpholino group; a heterocycloalkylalkyl group represents a hexahydropyranalkyl, piperidylalkyl And a morpholinoalkyl group Arylalkyl groups represent phenylalkyl, ethylenedioxyphenylalkyl and naphthylalkyl groups; heteroarylalkyl groups include thienylalkyl, pyridylalkyl, furylalkyl, pyrazolylalkyl, benzothienylalkyl, dihydrobenzofuranalkyl and benzimidazole An aryloxy group represents a phenoxy and naphthyloxy group; an arylalkoxy group represents a phenylalkoxy and naphthylalkoxy group; and an aryloxyalkyl group represents a phenoxyalkyl group; A compound of formula (I) above, wherein the group is optionally substituted as described in any one of claims 1-6. Formula (IA) [wherein A represents a saturated heterocyclic group which is either a 5- or 6-membered monocyclic group or a bicyclic group not more than 10-membered, and these rings At least two of the members are nitrogen atoms, the others may be the same or different and are carbon members or heterocyclic members selected from O, N and S, the heterocyclic ring A being Optionally substituted with one or more groups XA1, XA2 or XA3, selected from halogen atoms, alkyl, alkoxy or alkylthio groups, or thienyl groups (optionally substituted with alkyl groups);
A1, A2, A3 and A4 may be the same or different, and may be a hydrogen atom, a halogen atom, and a hydroxyl, alkyl, alkoxy, nitro, cyano, phenyl and phenoxy group, a carboxyl group (this is Are free, salted, esterified with an alkyl group or amidated with the group NA6A7), wherein A6 and A7 may be the same or different Optionally selected from hydrogen, and alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl and heteroarylalkyl groups, or A6 and A7 together with the nitrogen atom to which they are attached. To form a 5- or 6-membered cyclic group,
Two consecutive groups of A1, A2, A3 and A4 together with the benzimidazole group to which they are attached are identical or different selected from O, N and S Good, capable of forming a ring based on 5- to 6-membered carbon containing one or more heteroatoms;
A5 represents a hydrogen atom or an alkyl group,
All the above phenyl, phenoxy, cycloalkyl and heteroarylalkyl groups are optionally halogen atoms and hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino Substituted with one or more groups selected from: phenylalkylamino, carboxyl (which is free, salted or esterified), and a dioxole group;
All the above alkyl, alkoxy and alkylthio groups are linear or branched and contain no more than 6 carbon atoms]
Which is a compound of formula (I) according to any one of claims 1 to 7,
The compounds of the formula (IA) are all of the possible racemic, enantiomeric or diastereoisomeric forms and also of the formula (IA) with inorganic and organic acids or with inorganic and organic bases A compound of formula (I) above which may be an addition salt of a compound of Formula (IAa) [wherein Aa represents a pyrazolyl, triazolyl or indazolyl group, and this heterocyclic ring Aa is a thienyl optionally substituted with a halogen atom, an alkyl, alkoxy or alkylthio group, and optionally an alkyl group Substituted with one or more groups XA1, XA2 or XA3 selected from the group;
A1a, A2a, A3a and A4a may be the same or different and are a hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy, nitro, cyano, phenyl and phenoxy group, and a carboxyl group (this is Free, salted, esterified with an alkyl group or amidated with the group NA6aA7a), wherein A6a and A7a may be the same or different Selected from a hydrogen atom and an alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, thienylalkyl and pyridylalkyl group, or A6a and A7a are Together with the nitrogen atom, pyrrolidinyl, pyrazoli Cycloalkenyl, pyrazolinyl, piperidyl, morpholino or when the on its second nitrogen atom, form a piperazinyl group substituted with an alkyl or phenyl group (optionally substituted themselves),
Two consecutive groups of A1a, A2a, A3a and A4a, together with the benzimidazole group to which they are attached, contain one or two oxygen atoms optionally substituted 5- It is understood that a ring based on a -6-membered carbon can be formed,
A5a represents a hydrogen atom or an alkyl group,
The above phenyl and phenoxy groups are optionally halogen atoms and hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, carboxyl (this is Free, salted or esterified), and substituted with one or more groups selected from dioxol groups,
All the above alkyl, alkoxy and alkylthio groups are linear or molecular and contain no more than 6 carbon atoms]
The compound of formula (I) according to any one of claims 1 to 8, which corresponds to
The compounds of the formula (IAa) are of the possible racemic, enantiomeric or diastereoisomeric forms and also of the formula (IAa) with inorganic and organic acids or with inorganic and organic bases A compound of formula (I) above which may be an addition salt of a compound of Formula (IAb):

[Where:
Ab is optionally a halogen atom and OH, alkyl, alkynyl, —OR6b (including alkoxy), —COR6b, —O—COR6b, —OS (O) nR6b, —O (CH2) n—CO—R6b, phenyl , Phenylalkyl, CF3, OCF3, NO2, CN, NY1bY2b, -NH-C (= O) NY1bY2b, acylamino (NH-CO-R6b), S (O) n-alk, S (O) n-NY1bY2b,- C (= O) -NY1bY2b, -C (= O) OR6b, -NH-C (= O) R6b, -NH-S (O) nR6b, -NH-C (= O) OR6b, -N (R6b) 1 or 2 selected from C (= O) NY1bY2b, -OC (= O) NY1bY2b and a thienyl group, all of which are optionally substituted It indicates pyrazolyl or indazolyl group of group substituted,
Here, in NY1bY2b, Y1b and Y2b may be the same or different, and hydrogen and optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy, phenylalkyl , Phenylalkylthio and naphthylalkyl, or Y1b and Y2b together with the nitrogen atom to which they are attached form a piperidyl, hexahydrofuran, morpholinyl or morpholinylalkyl group;
A1b, A2b, A3b and A4b may be the same or different, and are a hydrogen atom, a halogen atom, hydroxyl, alkyl, alkenyl, —OR6b (including alkoxy), —CO—R6b, —O—. COR6b, -OS (O) nR6b, -O (CH2) n-CO-R6b, nitro, cyano, furyl, thienyl, benzothienyl, naphthyl, thianthenyl, phenyl and phenoxy groups, and carboxyl groups (is this free? , Salted, esterified with an alkyl group or amidated with the group NA6bA7b), wherein A6b and A7b may be the same or different, Hydrogen and alkyl, alkoxyalkyl, phenoxyalkyl, phenyl, phenylal , Cycloalkylalkyl, cycloalkyl, furylalkyl, naphthylalkyl, thienylalkyl, piperidylalkyl, pyridylalkyl, benzothienylalkyl, pyrazolylalkyl, dihydrobenzofuranalkyl, hexahydropyranalkyl, ethylenedioxyphenylalkyl and benzoimidazolylalkyl groups ( All these groups are optionally substituted) or A6b and A7b together with the nitrogen atom to which they are attached form a pyrrolidinyl, morpholino or piperazinyl group, The piperazinyl group is optionally substituted on its second nitrogen atom with an alkyl group (which is itself optionally substituted);
Two consecutive groups of A1b, A2b, A3b and A4b, together with the benzimidazole group to which they are attached, an optionally substituted 4,5-ethylenedioxybenzimidazole group, or To form a 4,5-methylenedioxybenzimidazole group substituted by
A5b represents a hydrogen atom,
All the above groups, including alkyl, alkenyl, phenyl, phenoxy, furyl, thienyl, piperidyl, pyridyl, pyrazolyl and benzimidazolyl are optionally substituted with halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino. , Phenylamino, phenylalkylamino, acylamino (NH—COR6b), —C (═O) OR6b, acyl-C (═O) R6b, hydroxyalkyl, carboxyalkyl, phenoxyalkyl, S (O) n-alk, S (O) n-NH2, S (O) n-NH (alk), S (O) n-N (alk) 2, CF3, OCF3, NO2, CN, phenyl (optionally one or more Substituted with halogen atoms), thienyl, pheno One or more groups selected from cis, phenylalkoxy, —C (═O) —NH 2, —C (═O) —NH (alk) and C (═O) —N (alk) 2 groups Has been replaced,
n represents an integer of 0 to 2,
R6b represents hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, pyridyl, thienyl, naphthyl, isoxazole, adamentyl, quinoline, quinolone, dihydroquinolone, -NH-phenyl, phenylalkyl and cycloalkylalkyl, All groups are optionally morpholino, piperidyl, or phenyl (optionally per se halogen atoms, and cyano, CF3, OCF3, alkyl, phenyl-S (O) n-alk-phenyl, alkoxy, NH2, NHalk, N Substituted with one or more groups selected from (alk) 2, SO2NH2, SO2Nalk or SO2N (alk) 2 groups,
All the above alkyl, alkenyl, alkoxy and alkylthio groups are straight-chain or branched and contain no more than 10 carbon atoms,
Wherein all phenyl groups of the above groups are optionally further substituted with a dioxole group].
The compounds of the formula (IAb) are all of the possible racemic, enantiomeric or diastereoisomeric forms and also of the formula (IAb) with inorganic and organic acids or with inorganic and organic bases A compound of formula (I) above which may be an addition salt of a compound of Formula (IAb) wherein Ab is optionally a halogen atom and OH, alkyl, alkynyl, alkoxy, phenyl, phenylalkyl, CF3, OCF3, NO2, CN, NY1bY2b, -NH-C (= O) NY1bY2b , Acylamino (NH-CO-R6b), S (O) n-alk, S (O) n-NY1bY2b, -C (= O) -NY1bY2b, -C (= O) OR6b, -NH-C (= O ) R6b, -NH-S (O) nR6b, -NH-C (= O) OR6b, -N (R6b) C (= O) NY1bY2b, -OC (= O) NY1bY2b, and thienyl (optionally substituted) A pyrazolyl or indazolyl group substituted by one or two groups selected from the group
Here, in NY1bY2b, Y1b and Y2b may be the same or different, and hydrogen and optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy, phenylalkyl, Selected from phenylalkylthio and naphthylalkyl, or Y1b and Y2b together with the nitrogen atom to which they are attached form a piperidyl, hexahydrofuran, morpholinyl or morpholinylalkyl group;
A1b, A2b, A3b and A4b may be the same or different and are a hydrogen atom, a halogen atom, hydroxyl, alkyl, alkenyl, alkoxy, nitro, cyano, furyl, thienyl, benzothienyl, naphthyl, thiantenyl , Phenyl and phenoxy groups, and carboxyl groups (which are free, salted, esterified with an alkyl group or amidated with the group NA6bA7b), wherein A6b And A7b may be the same or different and are hydrogen and alkyl, alkoxyalkyl, phenoxyalkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, naphthylalkyl, thienylalkyl, piperidyl Selected from alkyl, pyridylalkyl, benzothienylalkyl, pyrazolylalkyl, dihydrobenzofuranalkyl, hexahydropyranalkyl, ethylenedioxyphenylalkyl and benzoimidazolylalkyl groups, all of which are optionally substituted, Alternatively, A6b and A7b together with the nitrogen atom to which they are attached form a pyrrolidinyl, morpholino, or piperazinyl group, which is optionally on its second nitrogen atom an alkyl group ( Itself is optionally substituted),
Two consecutive groups of A1b, A2b, A3b and A4b, together with the benzimidazole group to which they are attached, an optionally substituted 4,5-ethylenedioxybenzimidazole group, or A 4,5-methylenedioxybenzimidazole group substituted by
A5b represents a hydrogen atom,
All the above groups, including alkyl, alkenyl, phenyl, phenoxy, furyl, thienyl, piperidyl, pyridyl, pyrazolyl and benzimidazolyl are optionally substituted with halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino. , Phenylamino, phenylalkylamino, acylamino (NH—COR6b), —C (═O) OR6b, acyl-C (═O) R6b, hydroxyalkyl, carboxyalkyl, phenoxyalkyl, S (O) n-alk, S (O) n-NH2, S (O) n-NH (alk), S (O) n-N (alk) 2, CF3, OCF3, NO2, CN, phenyl (optionally one or more Substituted with halogen atoms), thienyl, pheno One or more groups selected from di, phenylalkoxy, —C (═O) —NH 2, —C (═O) —NH (alk), and C (═O) —N (alk) 2 groups Is replaced with
n represents an integer of 0 to 2,
R6b represents hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, phenylalkyl and cycloalkylalkyl;
All the above alkyl, alkenyl, alkoxy and alkylthio groups are straight-chain or branched and contain no more than 10 carbon atoms,
11. All the phenyl groups of the above groups are optionally substituted with a dioxole group], which is a compound of formula (I) according to any one of claims 1-10,
The compounds of the formula (IAb) are all of the possible racemic, enantiomeric or diastereoisomeric forms and also of the formula (IAb) with inorganic and organic acids or with inorganic and organic bases A compound of formula (I) above which may be an addition salt of a compound of Formula (IAb) wherein Ab represents a pyrazolyl group substituted with one or two groups, wherein one group is hydrogen, a halogen atom, and alkyl, alkynyl, —COR6b, phenyl, Phenylalkyl, CF3, NO2, CN, NY1bY2b, -NH-C (= O) NY1bY2b, NH-CO-R6b, S (O) n-alk, S (O) n-NY1bY2b, -C (= O)- NY1bY2b, -C (= O) OR6b, -NH-C (= O) R6b, -NH-S (O) nR6b, -NH-C (= O) OR6b, -N (R6b) C (= O) NY1bY2b And thienyl groups (all these groups are optionally substituted),
And other groups are OH, -OR6b, -O-COR6b, -OS (O) nR6b, -O (CH2) n-CO-R6b and -OC (= O) NY1bY2b groups (all these groups are Is replaced by) and
Here, in NY1bY2b, Y1b and Y2b may be the same or different, and hydrogen and optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy, phenylalkyl , Phenylalkylthio and naphthylalkyl, or Y1b and Y2b together with the nitrogen atom to which they are attached form a piperidyl, hexahydrofuran, morpholinyl or morpholinylalkyl group;
A1b, A2b, A3b and A4b may be the same or different, two of them are hydrogen and the other two are the same or different. Hydrogen atom, halogen atom, hydroxyl, alkyl, alkenyl, -OR6b (including alkoxy), -CO-R6b, -O-COR6b, -OS (O) nR6b, -O (CH2) n-CO-R6b , Nitro, cyano, furyl, thienyl, benzothienyl, naphthyl, thiantenyl, phenyl and phenoxy groups, and carboxyl groups (which are free, salted, esterified with alkyl groups, or group NA6bA7b Wherein A6b and A7b may be the same or different , Hydrogen, and alkyl, alkoxyalkyl, phenoxyalkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, naphthylalkyl, thienylalkyl, piperidylalkyl, pyridylalkyl, benzothienylalkyl, pyrazolylalkyl, dihydrobenzofuranalkyl, Selected from hexahydropyranalkyl, ethylenedioxyphenylalkyl and benzimidazolylalkyl groups, all of which are optionally substituted, or A6b and A7b together with the nitrogen atom to which they are attached To form a pyrrolidinyl, morpholino or piperazinyl group, which is optionally on its second nitrogen atom an alkyl group (in itself case). Ri is substituted with has been replaced),
A5b represents a hydrogen atom,
All the above groups, including alkyl, alkenyl, phenyl, phenoxy, furyl, thienyl, piperidyl, pyridyl, pyrazolyl and benzimidazolyl are optionally substituted with halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino. , Phenylamino, phenylalkylamino, acylamino (NH—COR6b), —C (═O) OR6b, acyl-C (═O) R6b, hydroxyalkyl, carboxyalkyl, phenoxyalkyl, S (O) n-alk, S (O) n-NH2, S (O) n-NH (alk), S (O) n-N (alk) 2, CF3, OCF3, NO2, CN, phenyl (optionally one or more Substituted with halogen atoms), thienyl, pheno One or more groups selected from cis, phenylalkoxy, —C (═O) —NH 2, —C (═O) —NH (alk) and C (═O) —N (alk) 2 groups Has been replaced,
n represents an integer of 0 to 2,
R6b represents hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, pyridyl, thienyl, naphthyl, isoxazole, adamentyl, quinoline, quinolone, dihydroquinolone, -NH-phenyl, phenylalkyl and cycloalkylalkyl, All groups are optionally morpholino, piperidyl or phenyl (optionally per se halogen atoms and cyano, CF3, OCF3, alkyl, phenyl-S (O) n-alk-phenyl, alkoxy, NH2, NHalk, N (Alk) 2, SO 2 NH 2, SO 2 Nalk or SO 2 N (alk) 2 group)
All the above alkyl, alkenyl, alkoxy and alkylthio groups are linear or molecular and contain no more than 10 carbon atoms,
12. All the phenyl groups of the above groups are optionally further substituted with a dioxole group], which is a compound of formula (I) according to any one of claims 1 to 11,
The compounds of the formula (IAb) are all of the possible racemic, enantiomeric or diastereoisomeric forms and also of the formula (IAb) with inorganic and organic acids or with inorganic and organic bases A compound of formula (I) above which may be an addition salt of a compound of Formula (IAb) wherein Ab represents a pyrazolyl or indazolyl group optionally substituted with a halogen atom and one or more groups selected from alkyl, alkoxy and thienyl groups;
A1b, A2b, A3b and A4b may be the same or different and are a hydrogen atom, a halogen atom, a group of the following type: hydroxyl, alkyl, optionally phenyl (in itself, optionally one Or substituted with alkenyl, alkoxy, nitro, cyano, furyl, optionally substituted with acylCOalk, thienyl, benzothienyl, naphthyl, thiantenyl, optionally substituted Selected from phenyl and phenoxy; and carboxyl groups (which are free, salted, esterified with an alkyl group or amidated with the group NA6bA7b), wherein A6b and A7b may be the same or different, and water And groups of the following types: alkyl, alkoxyalkyl containing no more than 6 carbon atoms, phenoxyalkyl optionally substituted with acylamino (NH-C (O) alk), phenyl, optionally substituted Phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, optionally substituted with one or more alkyl groups, naphthylalkyl, optionally substituted with alkyl or thienyl, optionally with carboxyl groups (this is Piperidylalkyl, which is free, salted or esterified with an alkyl group), optionally substituted with one or more groups selected from halogen and CF3 Alkyl, benzothienyl Alkyl, pyrazolylalkyl, dihydrobenzofuranalkyl, hexahydropyranalkyl, ethylenedioxyphenylalkyl, optionally substituted with one or more alkyl groups, and optionally substituted with one or more alkyl groups Selected from benzimidazolyl alkyl,
Or, A6b and A7b together with the nitrogen atom to which they are attached form a pyrrolidinyl, morpholino or piperazinyl group, which is optionally substituted with an alkyl group on its second nitrogen atom Has been
Two consecutive groups of A1b, A2b, A3b and A4b, together with the benzimidazole group to which they are attached, an optionally substituted 4,5-ethylenedioxybenzimidazole group, or A 4,5-methylenedioxybenzimidazole group substituted by
R5a represents a hydrogen atom,
The above phenyl, phenoxy and phenylalkyl groups are optionally halogen atoms, hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino and NH-COalk groups, carboxyl groups (this is Free, salted, or esterified with an alkyl group), and hydroxyalkyl, carboxyalkyl, phenoxyalkyl, alkylthio, SO2alk, SO2NH2, SO2-NH (alk), SO2-N (alk ) 2, CF 3, OCF 3, NO 2, CN, phenyl (which is itself optionally substituted with one or more halogen atoms), thienyl, phenoxy, phenylalkoxy, —C (═O) —NH 2, —C ( O) -NH (alk), C (= O) -N (alk) is selected from 2 and C (O) CH3 group is substituted with one or more groups,
All the above alkyl or alk, alkenyl, alkoxy and alkylthio groups are linear or molecular chain and contain no more than 4 carbon atoms,
All phenyl groups of the above groups are optionally further substituted with a dioxole group], which is a compound of formula (I) according to any one of claims 1 to 12,
The compounds of the formula (IAb) are all of the possible racemic, enantiomeric or diastereoisomeric forms and also of the formula (IAb) with inorganic and organic acids or with inorganic and organic bases A compound of formula (I) above which may be an addition salt of a compound of Formula (IAb) [wherein Ab, A1b, A2b, A3b, A4b and A5b have the meanings described in any of claims 1 to 13,
And when one of A1b, A2b, A3b and A4b represents a carboxyl group amidated with the group NA6bA7b, one of A6b and A7b is a hydrogen atom or an alkyl group, and the other of A6b and A7b is A6b and Selected from the definitions set forth for A7b, or A6b and A7b together with the nitrogen atom to which they are attached form a 5- or 6-membered cyclic group;
Other substituents of the product of formula (I) have the meanings given in any of claims 1 to 13]
The compound of formula (I) according to any one of claims 1 to 13, which corresponds to
The compounds of the formula (IAb) are all of the possible racemic, enantiomeric or diastereoisomeric forms and also of the formula (IAb) with inorganic and organic acids or with inorganic and organic bases A compound of formula (I) above which may be an addition salt of a compound of A compound of formula (I) according to claim 1, wherein
X, W, Y and Z, two or three of them represent CH, and the others are selected from the definition of CR2 or CR3, and can form a dioxole group if appropriate;
R2, R3 and the other substituents of the compound of formula (I) have the definitions described in any of claims 1-14,
The compounds of the formula (I) are of all possible racemic, enantiomeric or diastereoisomeric forms, and also of the formula (I) with inorganic and organic acids or with inorganic and organic bases. A compound of formula (I) above which may be an addition salt of a compound of Formula (IAb):

[Where:
Ab represents a pyrazolyl or indazolyl group optionally substituted with a halogen atom and one or more groups selected from alkyl, alkoxy and thienyl groups;
A1b, A2b, A3b and A4b may be the same or different, and are a hydrogen atom, halogen atom, hydroxyl, alkyl and alkoxy, nitro, cyano, phenyl and phenoxy group, and a carboxyl group (this is Free, salted, esterified with an alkyl group or amidated with the group NA6bA7b), wherein A6b and A7b may be the same or different Optionally selected from alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl and furylalkyl groups, or A6b and A7b together with the nitrogen atom to which they are attached, pyrrolidinyl, On the morpholino, or optionally on its second nitrogen atom Forming a piperazinyl group substituted with an alkyl group,
Two consecutive groups of A1b, A2b, A3b and A4b together with the benzimidazole group to which they are attached are optionally substituted 4,5-ethylenedioxybenzimidazole groups or 4,4 It is understood that a 5-methylenedioxybenzimidazole group can be formed,
R5a represents a hydrogen atom,
The above phenyl and phenoxy groups are optionally halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, and carboxyl groups (which are free or salt Or is esterified) and is substituted with one or more groups selected from
All the above alkyl, alkoxy and alkylthio groups are linear or molecular and contain no more than 4 carbon atoms]
Which is a compound of formula (I) according to claim 1,
The compounds of the formula (IAb) are all of the possible racemic, enantiomeric or diastereoisomeric forms and also of the formula (IAb) with inorganic and organic acids or with inorganic and organic bases A compound of formula (I) above which may be an addition salt of a compound of 17. A compound of formula (I) according to any one of claims 1 to 16, corresponding to the following formula:
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-methylamide 2- ( 1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-ethylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-isopropylamide 2- (1H -Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenethylamide 2- (1H -Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-morpho Noamido 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (N′-methylpiperazino) amide 2- (1H-indazol-3-yl) -1H-benzimidazole-5 Carboxylic acid N-pyrrolidinoamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (isobutyl) amide 2- (1H-indazol-3-yl) -1H-benzimidazole -5-carboxylic acid N- (cyclohexylmethyl) amide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (2-furfuryl) amide 2- (1H-indazole-3- Yl) -1H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide methyl 2- (1 H-indazol-3-yl) -3H-benzimidazole-5-carboxylate 5,6-dimethyl-2- (1H-indazol-3-yl) -1H-benzimidazole 5-methoxy-2- (1H-indazole) -3-yl) -1H-benzimidazole 2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 5-bromo 2- (1H-indazol-3-yl) -3H-benzimidazole 2- (5-Ethoxy-2H-pyrazol-3-yl) -1H-benzimidazole-4-carboxylic acid 5,6-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -1H-benzo Imidazole 5,6-dimethyl-2- (5-thiophen-2-yl-2H-pyrazol-3-yl) -1H-benzimidazole 2- (4-Bromo-2H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole 2- (5-ethyl-2H-pyrazol-3-yl) -5,6-dimethyl-1H- Benzimidazole 2- (5-ethyl-2H-pyrazol-3-yl) -4,5-ethylenedioxy-1H-benzimidazole 2- (5-ethyl-2H-pyrazol-3-yl) -5-methoxy- 1H-benzimidazole 2- (5-ethyl-2H-pyrazol-3-yl) -4-hydroxy-1H-benzimidazole 2- (5-ethyl-2H-pyrazol-3-yl) -5-bromo-1H- Benzimidazole 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4- (aminosulfonyl) benzylamide 2- (1H- Ndazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-bromobenzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4- (methanesulfonyl) benzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-nitrobenzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-methyl Benzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (6-chloropyridin-3-ylmethyl) amide 2- (1H-indazol-3-yl) -1H-benzimidazole -5-carboxylic acid (2,3-dihydrobenzofuran-5-ylmethyl) amide -(1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2- (methylsulfanyl) benzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid ( Benzo [b] thiophen-3-ylmethyl) amide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-methylbenzylamide 2- (1H-indazol-3-yl) -1H -Benzimidazole-5-carboxylic acid 3-chlorobenzylamide 2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 2- (methylsulfanyl) benzylamide. 17. A compound of formula (I) according to any one of claims 1 to 16, corresponding to the following formula:
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid benzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-methylamide 2- ( 1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-ethylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-isopropylamide 2- (1H -Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenethylamide 2- (1H -Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-morpho Noamido 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (N′-methyl-piperazino) amide 2- (1H-indazol-3-yl) -1H-benzimidazole 5-Carboxylic acid N-pyrrolidinoamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (isobutyl) amide 2- (1H-indazol-3-yl) -1H- Benzimidazole-5-carboxylic acid N- (cyclohexylmethyl) amide 2- (1H-indazol-3-yl) -1H-benzimidazol-5-carboxylic acid N- (2-furfuryl) amide 2- (1H-indazole- 3-yl) -1H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide 5-methoxy 2- (1H-indazol-3-yl) -1H-benzimidazole 2- (5-ethyl-2H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole 2- (5-ethyl- 2H-pyrazol-3-yl) -4,5-ethylenedioxy-1H-benzimidazole 2- (5-ethyl-2H-pyrazol-3-yl) -5-methoxy-1H-benzimidazole 2- (5- Ethyl-2H-pyrazol-3-yl) -4-hydroxy-1H-benzimidazole 2- (5-Ethyl-2H-pyrazol-3-yl) -5-bromo-1H-benzimidazole. 17. A compound of formula (I) according to any one of claims 1 to 16, corresponding to the following formula:
2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4- (aminosulfonyl) benzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4-Bromobenzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 4- (methanesulfonyl) benzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole -5-carboxylic acid 4-nitrobenzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 2-methylbenzylamide 2- (1H-indazol-3-yl) -1H- Benzimidazole-5-carboxylic acid (6-chloropyridin-3-ylmethyl) amide 2 (1H-Indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (2,3-dihydrobenzofuran-5-ylmethyl) amide 2- (1H-indazol-3-yl) -1H-benzimidazole-5 -Carboxylic acid 2- (methylsulfanyl) benzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (benzo [b] thiophen-3-ylmethyl) amide 2- (1H-indazole) -3-yl) -1H-benzimidazole-5-carboxylic acid 3-methylbenzylamide 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid 3-chlorobenzylamide 2- (1H -Indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 2- (me Rusurufaniru) benzylamide. A process for the preparation of a compound of formula (I) according to claim 1 comprising the formula (D):
R1′-COOH (D)
Wherein R1 ′ has the meaning as defined in claim 1 for R1, wherein a possible reactive functional group is optionally protected with a protecting group] To the formula (II):
R1'-COOalk (II)
[Wherein R1 ′ has the above-mentioned meaning and alk represents an alkyl group] is converted into an acid ester, which is subjected to a reduction reaction to give a formula (III):
R1′-CH2OH (III)
[Wherein R1 ′ has the above-mentioned meaning] and is oxidized to give the formula (IV):
R1'-CHO (IV)
Wherein R1 ′ has the meaning described above,
A compound of formula (D) or a compound of formula (IV) as defined above is then converted to formula (V):

In which W ′, X ′, Y ′ and Z ′ have the meanings given in claim 1 for W, X, Y and Z, respectively, where possible reactive functional groups are Is protected with a protecting group according to formula (I ′):

Wherein A5 ′ has the meaning as claimed in claim 1 for A5, wherein possible reactive functional groups are optionally protected with protecting groups and R1 ′, W ′, X ′, Y ′ and Z ′ have the meanings described above],
The compound of formula (I ′) may be a compound of formula (I), and this compound is optionally and necessary to obtain a compound of formula (I) or other compounds of formula (I) Depending on, in any order, one or more of the following conversion reactions:
a) esterification reaction of acid functional group,
b) Saponification reaction of ester functional group to acid functional group,
c) oxidation reaction of alkylthio group to the corresponding sulfoxide or sulfone,
d) Conversion reaction of ketone functional group to oxime functional group,
e) reduction reaction of a free or esterified carboxyl function to an alcohol function,
f) Conversion reaction of alkoxy functional group to hydroxyl functional group, or conversion reaction of hydroxyl functional group to alkoxy functional group,
g) oxidation reaction of alcohol functionality to aldehyde, acid or ketone functionality,
h) conversion reaction of nitrile group to tetrazolyl,
i) removal reaction of a protecting group which may be supported on the protected reactive functional group;
j) a salt-forming reaction with an inorganic or organic acid or with a base to obtain the corresponding salt;
k) subjecting to a resolving reaction in which the racemic state is resolved to the resolving compound, thus obtaining the compound of formula (I) in any possible racemic, enantiomeric or diastereomeric isomeric form. Manufacturing method. A process for the preparation of a compound of formula (I) according to claim 1 corresponding to formula (IA), comprising formula (D):
A'-COOH (D)
Wherein A ′ has the meaning as defined in claim 5 for A, wherein possible reactive functional groups are optionally protected with protecting groups, Attached to formula (II):
A'-COOalk (II)
[Wherein A ′ has the above-mentioned meaning and alk represents an alkyl group], which is an acid ester, which is subjected to a reduction reaction to obtain a compound represented by the formula (III):
A'-CH2OH (III)
[Wherein A ′ has the above-mentioned meaning] and this is oxidized to form the formula (IV):
A'-CHO (IV)
Wherein A ′ has the above-mentioned meaning, and a compound of formula (D) or a compound of formula (IV) as defined above is represented by formula (V):

[Wherein A1 ′, A ′, A3 ′ and A4 ′ have the meanings described in claim 1 for A1, A2, A3 and A4, respectively, where possible reactive functional groups are Is protected with a protecting group according to formula (IA ′):

[Wherein A5 ′ has the meaning as defined in claim 5 for A5, where possible reactive functional groups are optionally protected with protecting groups, and A1 ′, A2 ′, A3 'And A4' have the above-mentioned meanings],
The compound of formula (IA ′) may be a compound of formula (IA) and this compound is optionally and necessary to obtain a compound of formula (IA) or other compounds of formula (IA) Can be subjected in any order to one or more conversion reactions selected from reactions a) to k) according to claim 20,
Thus, the process as described above, wherein the resulting compound of formula (IA) is in any possible racemic, enantiomeric or diastereoisomeric form.   17. A compound of formula (I) according to any one of claims 1 to 16 as a medicament and also with pharmaceutically acceptable inorganic and organic acids or pharmaceutically acceptable inorganic bases and organics. Addition salt of the compound of formula (I) with a base.   20. A compound of formula (I) according to any one of claims 17 to 19 as a medicament and also with pharmaceutically acceptable inorganic and organic acids or pharmaceutically acceptable inorganic bases and organics. Addition salt of the compound of formula (I) with a base.   20. As an active ingredient, at least one compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt of this compound, or a prodrug of this compound, and a pharmaceutically acceptable A pharmaceutical composition comprising a supported carrier.   20. Use of a compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt of this compound, for the manufacture of a medicament intended for inhibition of kinase protein activity.   21. Use of a compound of formula (I) according to any one of claims 1 to 19 for the manufacture of a medicament for the treatment or prevention of diseases characterized by dysregulation of kinase protein activity.   26. Use according to claim 25, wherein the kinase protein is a tyrosine kinase protein.   26. Use according to claim 25, wherein the kinase protein is selected from the following group: FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, flt-1, IGF-1R, KDR, PDGFR, tie2 and VEGFR.   26. Use according to claim 25, wherein the kinase protein is KDR.   26. Use according to claim 25, wherein the kinase protein is tie2.   26. Use according to claim 25, wherein the kinase protein is in a cell culture.   26. Use according to claim 25, wherein the kinase protein is a mammalian kinase protein.   The following groups: abnormal vascular proliferation, fibrotic disorders, abnormal mesangial cell proliferation, metabolic disorders, allergies, asthma, thrombosis, nervous system diseases, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration and Use of a compound of formula (I) according to any one of claims 1 to 19 for the manufacture of a medicament for the treatment or prevention of diseases selected from cancer.   The following groups: vascular proliferative disorder, fibrotic disorder, "mesangial" cell proliferative disorder, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration and a drug for the treatment or prevention of diseases selected from cancer Use of a compound of formula (I) according to any one of claims 1 to 19 for the manufacture.   21. Use of a compound of formula (I) according to any one of claims 1 to 19 for the manufacture of a medicament for the prevention or treatment of diseases involving uncontrolled angiogenesis.   20. Use of a compound of formula (I) according to any one of claims 1 to 19 for the manufacture of a medicament for the treatment of diseases in oncology.   Use of a compound of formula (I) according to any one of claims 1 to 19 for the manufacture of a medicament for the treatment of cancer.   37. Use according to claim 36 for the treatment of solid tumors.   39. Use according to claim 37 or 38 for the treatment of cancer resistant to cytotoxic agents.   For the treatment of breast cancer, stomach cancer, ovarian cancer, colon cancer, lung cancer, brain tumor, laryngeal cancer, lymphatic cancer, urogenital tract cancer including bladder and prostate, bone cancer and pancreatic cancer Use according to claim 37 or 38 for.   39. Use according to claim 37 or 38 for the treatment of breast cancer, colon cancer or lung cancer.   Use of a compound of formula (I) according to any one of claims 1 to 19 for the manufacture of a medicament for cancer chemotherapy.   21. Use of a compound of formula (I) according to any one of claims 1 to 19 for the manufacture of a medicament intended for cancer chemotherapy, used alone or in combination.   20. A compound of formula (I) according to any one of claims 1 to 19 as a kinase inhibitor.   20. A compound of formula (I) according to any one of claims 1 to 19 as a KDR inhibitor.   20. A compound of formula (I) according to any one of claims 1 to 19 as a tie2 inhibitor.